Substituted heterocyclic derivatives useful as antidiabetic and antiobesity agents and method

ABSTRACT

wherein 
         Z 1  is (CH 2 ) q  or C═O;    Z 2  is (CH 2 ) p  or C═O;    D is —CH═ or C═O or (CH 2 ) m  where m is 0, 1, 2 or 3; n=0, 1 or 2; p=1 or 2; q=0, 1 or 2; Q is C or N;    A is (CH 2 ) x  where x is 1 to 5, or A is (CH 2 ) x   1 , where x 1  is 1 to 5 with an alkenyl bond or an alkynyl bond embedded anywhere in the chain, or A is —(CH 2 ) x   2 —O—(CH 2 ) x   3 — where x 2  is 0 to 5 and x 3  is 0 to 5, provided that at least one of x 2  and x 3  is other than 0;    B is a bond or is (CH 2 ) x   4  where x 4  is 1 to 5; X is CH or N;    X 2  is C, N, O or S;    X 3  is C, N, O or S;    X 4  is C, N, O or S;    X 5  is C, N, O or S;    X 6  is C, N, O or S; 
 
provided that at least one of X 2 , X 3 , X 4  X 5  and X 6  is N; and at least one of X 2 , X 3 , X 4  X 5  and X 6  is C. 
   R 1  is H or alkyl;    R 2  is H, alkyl, alkoxy, halogen, amino, substituted amino or cyano;    R 2a , R 2b  and R 2c  may be the same or different and are selected from H, alkyl, alkoxy, halogen, amino, substituted amino or cyano; and    R 3 , E, Z and Y are as defined herein.

This application is a Divisional of U.S. patent application Ser. No.10/616,365, filed Jul. 8, 2003, that claims the benefit of U.S.Provisional Application 60/394,508, filed Jul. 9, 2002 which areincorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to novel substituted heterocyclicderivatives which modulate blood glucose levels, triglyceride levels,insulin levels and non-esterified fatty acid (NEFA) levels, and thus areparticularly useful in the treatment of diabetes and obesity, and to amethod for treating diabetes, especially Type 2 diabetes, as well ashyperglycemia, hyperinsulinemia, hyperlipidemia, obesity,atherosclerosis and related diseases employing such substituted acidderivatives alone or in combination with another antidiabetic agentand/or a hypolipidemic agent and/or other therapeutic agents.

DESCRIPTION OF THE INVENTION

In accordance with the present invention, substituted heterocyclicderivatives are provided which have the structure

wherein

Z¹ is (CH₂)_(q) or C═O;

Z² is (CH₂)_(p) or C═O;

wherein D is —CH═ or C═O or (CH₂)_(m) where m is 0, 1, 2 or 3;

n=0, 1 or 2; p=1 or 2; q=0, 1 or 2;

Q is C or N;

A is (CH₂)_(x) where x is 1 to 5, or A is (CH₂)_(x) ¹, where x¹ is 1 to5 with an alkenyl bond or an alkynyl bond embedded anywhere in thechain, or A is —(CH₂)_(x) ²—O—(CH₂)_(x) ³— where x² is 0 to 5 and x³ is0 to 5, provided that at least one of x² and x³ is other than 0;

B is a bond or is (CH₂)_(x) ⁴ where x⁴ is 1 to 5;

X is CH or N;

X₂ is C, N, O or S;

X₃ is C, N, O or S;

X₄ is C, N, O or S;

X₅ is C, N, O or S;

X₆ is C, N, O or S;

provided that at least one of X₂, X₃, X₄ X₅ and X₆ is N; and at leastone of X₂, X₃, X₄ X₅ and X₆ is C.

In each of X through X₆, as defined above, C may include CH.

R¹ is H or alkyl;

R² is H, alkyl, alkoxy, halogen, amino, substituted amino or cyano;

R^(2a), R^(2b) and R^(2c) may be the same or different and are selectedfrom H, alkyl, alkoxy, halogen, amino, substituted amino or cyano;

R³ is selected from H, alkyl, arylalkyl, aryloxycarbonyl,alkyloxycarbonyl, alkynyloxycarbonyl, alkenyloxycarbonyl, arylcarbonyl,alkylcarbonyl, aryl, heteroaryl, cycloheteroalkyl, heteroarylcarbonyl,heteroaryl-heteroarylalkyl, alkylcarbonylamino, heteroaryloxycarbonyl,cycloheteroalkyloxycarbonyl, heteroarylalkyl, aminocarbonyl, substitutedaminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, heteroarylalkenyl,cycloheteroalkyl-heteroarylalkyl; hydroxyalkyl, alkoxy,alkoxyaryloxycarbonyl, arylalkyloxycarbonyl, alkylaryloxycarbonyl,arylheteroarylalkyl, arylalkylarylalkyl, aryloxyarylalkyl,haloalkoxyaryloxycarbonyl, alkoxycarbonylaryloxycarbonyl,aryloxyaryloxycarbonyl, arylsulfinylarylcarbonyl, arylthioarylcarbonyl,alkoxycarbonylaryloxycarbonyl, arylalkenyloxycarbonyl,heteroaryloxyarylalkyl, aryloxyarylcarbonyl, arylcarbonylamino,heteroarylcarbonylamino, alkoxycarbonylamino, aryloxycarbonylamino,heteroaryloxycarbonylamino, heteroarylheteroarylcarbonyl, alkylsulfonyl,alkenylsulfonyl, heteroaryloxycarbonyl, cycloheteroalkyloxycarbonyl,heteroarylalkyl, aminocarbonyl, substituted aminocarbonyl,alkylaminocarbonyl, arylaminocarbonyl, heteroarylalkenyl,cycloheteroalkyl-heteroarylalkyl; hydroxyalkyl, alkoxy,alkoxyaryloxycarbonyl, arylalkyloxycarbonyl, alkylaryloxycarbonyl,arylheteroarylalkyl, arylalkylarylalkyl, aryloxyarylalkyl,haloalkoxyaryloxycarbonyl, alkoxycarbonylaryloxycarbonyl,aryloxyaryloxycarbonyl, arylsulfinylarylcarbonyl, arylthioarylcarbonyl,alkoxycarbonylaryloxycarbonyl, arylalkenyloxycarbonyl,heteroaryloxyarylalkyl, aryloxyarylcarbonyl,aryloxyarylalkyloxycarbonyl, arylalkenyloxycarbonyl, arylalkylcarbonyl,aryloxyalkyloxycarbonyl, arylalkylsulfonyl, arylthiocarbonyl,arylalkenylsulfonyl, heteroarylsulfonyl, arylsulfonyl, alkoxyarylalkyl,heteroarylalkoxycarbonyl, arylheteroarylalkyl, alkoxyarylcarbonyl,aryloxyheteroarylalkyl, heteroarylalkyloxyarylalkyl, arylarylalkyl,arylalkenylarylalkyl, arylalkoxyarylalkyl, arylcarbonylarylalkyl,alkylaryloxyarylalkyl, arylalkoxycarbonylheteroarylalkyl,heteroarylarylalkyl, arylcarbonylheteroarylalkyl,heteroaryloxyarylalkyl, arylalkenylheteroarylalkyl, arylaminoarylalkyl,aminocarbonylarylarylalkyl;

E is CH or N;

Z is (CH₂)_(x) ⁵ where x⁵ is 0 (i.e. a single or a double bond), 1 or 2(preferably 0 to 1); or Z is (CH₂)_(x) ⁶ where x⁶ is 2 to 5 (preferably2 or 3) where (CH₂)_(x) ⁶ includes an alkenyl (C═C) bond embedded withinthe chain or Z is —(CH₂)_(x) ⁷—O—(CH₂)_(x) ⁸— where x⁷ is 0 to 4(preferably 0 to 2) and x⁸ is 0 to 4 (preferably 0 to 2);

(CH₂)_(x), (CH₂)_(x) ¹, (CH₂)_(x) ² (CH₂)_(x) ³, (CH₂)_(x) ⁴, (CH₂)_(x)⁵, (CH₂)_(x) ⁶, (CH₂)_(x) ⁷, (CH₂)_(x) ⁸, (CH₂)_(m), (CH₂)_(n),(CH₂)_(p) and (CH₂)_(q) may be optionally substituted;

Y is CO₂R⁴ (where R⁴ is H or alkyl, or a prodrug ester) or Y is aC-linked 1-tetrazole, a phosphinic acid of the structureP(O)(OR^(4a))R⁵, (where R^(4a) is H or a prodrug ester, R⁵ is alkyl oraryl) or a phosphonic acid of the structure P(O)(OR^(4a))₂;

and all stereoisomers thereof, prodrug esters thereof, andpharmaceutically acceptable salts thereof.

Thus, the compounds of the invention include the structures:

Preferred are compounds of formula I of the invention having thestructures IA and IB

where X is CH.

where X is CH.

More preferred are compounds of formula I of the invention having thestructures IC and ID

where X=CH,

where X is CH, q=0, and Z is a single bond.

In the above compounds IC, it is most preferred that R¹ is alkyl,preferably CH₃; R^(2a) is alkyl, alkoxy or halogen, x² is 1 to 3; D is—CH═ or (CH₂)_(m) where m is 0 or (CH₂)_(m) is CH₂ or CH-alkyl, X is CH,X₂, X₃, X₄, X₅, and X₆ represent a total of 1, 2 or 3 nitrogens;(CH₂)_(n) is a bond or CH₂; p is 1; Z is a bond, q is 1; R³ isalkoxycarbonyl, aryl, heteroaryl, aryloxycarbonyl or arylalkyl; Y isCOR⁴; and n is 0.

In the above compounds ID, it is most preferred that R¹ is alkyl,preferably CH₃; R^(2a) is alkyl, alkoxy or halogen, x² is 1 to 3; D is—CH═ or (CH₂)_(m) where m is 0 or (CH₂)_(m) is CH₂ or CH-alkyl, X is CH,X₂, X₃, X₄, X₅, and X₆ represent a total of 1, 2 or 3 nitrogens;(CH₂)_(n) is a bond or CH₂; Z is a bond, q is 0 or 1; R³ isalkoxycarbonyl, aryl, heteroaryl, aryloxycarbonyl or arylalkyl; Y isCOR⁴; and n is 0.

Examples of

groups present in the compounds of the invention include, but are notlimited to

as well as those five-membered rings covered under the definition ofheteroaryl set out hereafter, with

being preferred.

Examples of

which may be present in the compounds of the invention include, but arenot limited to

being preferred.

Preferred compounds of the invention include the following:

In addition, in accordance with the present invention, a method isprovided for treating diabetes, especially Type 2 diabetes, and relateddiseases such as Type I diabetes, insulin resistance, hyperglycemia,hyperinsulinemia, elevated blood levels of fatty acids or glycerol,hyperlipidemia, obesity, hypertriglyceridemia, inflammation, Syndrome X,diabetic complications, dysmetabolic syndrome, atherosclerosis, andrelated diseases wherein a therapeutically effective amount of acompound of structure I is administered to a patient in need oftreatment.

In addition, in accordance with the present invention, a method isprovided for treating early malignant lesions (such as ductal carcinomain situ of the breast and lobular carcinoma in situ of the breast),premalignant lesions (such as fibroadenoma of the breast and prostaticintraepithelial neoplasia (PIN), liposarcomas and various otherepithelial tumors (including breast, prostate, colon, ovarian, gastricand lung), irritable bowel syndrome, Crohn's disease, gastric ulceritis,and osteoporosis and proliferative diseases such as psoriasis, wherein atherapeutically effective amount of a compound of structure I isadministered to a patient in need of treatment.

In addition, in accordance with the present invention, a method isprovided for treating diabetes and related diseases as defined above andhereinafter, wherein a therapeutically effective amount of a combinationof a compound of structure I and another type antidiabetic agent and/ora hypolipidemic agent, and/or lipid modulating agent and/or other typeof therapeutic agent, is administered to a human patient in need oftreatment.

In the above method of the invention, the compound of structure I willbe employed in a weight ratio to the antidiabetic agent (depending uponits mode of operation) within the range from about 0.01:1 to about100:1, preferably from about 0.5:1 to about 10:1.

The conditions, diseases, and maladies collectively referenced to as“Syndrome X” or Dysmetabolic Syndrome (as detailed in Johanson, J. Clin.Endocrinol. Metab., 1997, 82, 727-734, and other publications) includehyperglycemia and/or prediabetic insulin resistance syndrome, and ischaracterized by an initial insulin resistant state generatinghyperinsulinemia, dyslipidemia, and impaired glucose tolerance, whichcan progress to Type II diabetes, characterized by hyperglycemia, whichcan progress to diabetic complications.

The term “diabetes and related diseases” refers to Type II diabetes,Type I diabetes, impaired glucose tolerance, obesity, hyperglycemia,Syndrome X, dysmetabolic syndrome, diabetic complications andhyperinsulinemia.

The conditions, diseases and maladies collectively referred to as“diabetic complications” include retinopathy, neuropathy andnephropathy, and other known complications of diabetes.

The term “other type(s) of therapeutic agents” as employed herein refersto one or more antidiabetic agents (other than compounds of formula I),one or more anti-obesity agents, and/or one or more lipid-loweringagents, one or more lipid modulating agents (includinganti-atherosclerosis agents), and/or one or more antiplatelet agents,one or more agents for treating hypertension, one or more anti-cancerdrugs, one or more agents for treating arthritis, one or moreanti-osteoporosis agents, one or more anti-obesity agents, one or moreagents for treating immunomodulatory diseases, and/or one or more agentsfor treating anorexia nervosa.

The term “lipid-modulating” agent as employed herein refers to agentswhich lower LDL and/or raise HDL and/or lower triglycerides and/or lowertotal cholesterol and/or other known mechanisms for therapeuticallytreating lipid disorders.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the formula I of the present invention may be preparedaccording to the following general synthetic schemes, as well asrelevant published literature procedures that are used by one skilled inthe art. Exemplary reagents and procedures for these reactions appearhereinafter and in the working Examples. Protection and deprotection inthe Schemes below may be carried out by procedures generally known inthe art (see, for example, Greene, T. W. and Wuts, P. G. M., ProtectingGroups in Organic Synthesis, 3^(rd) Edition, 1999 [Wiley]).

The synthesis of some key intermediates required for the synthesis ofthe compounds in this patent are described in Scheme 1. An alcohol 1(R⁵(CH₂)_(x) ²OH) (which preferably is2-phenyl-5-methyl-oxazole-4-ethanol) is coupled with a hydroxy aryl- orheteroaryl-aldehyde 2 under standard Mitsunobu reaction conditions (e.g.Mitsunobu, O., Synthesis, 1981, 1) to furnish the key intermediatealdehyde 3. Alternatively, the alcohol 1 can be converted to itsmethanesulfonate ester 4 under standard conditions; the mesylate 4 canthen be used to alkylate the hydroxy aryl- or heteroaryl-aldehyde 2 tofurnish the aldehyde 3.

A synthesis of the pyrrolidine acids I is shown in Scheme 2. Treatmentof the aldehyde 3 with the Horner-Emmons reagent (CF₃CH₂O)₂P(O)CH₂CO₂CH₃5 (W. C. Still et al., Tetrahedron Lett. 1985, 24, 4405-5508) providesthe Z-alkenyl ester 6. This Z-alkenyl ester 6 is then reacted withN-trimethylsilylmethyl N-methoxymethyl benzylamine 7 under standardliterature conditions (e.g. J. S. Carey, J. Org. Chem., 2001, 66,2526-2529) to give the corresponding N-benzyl pyrrolidine-ester 8.Deprotection of the N-benzyl group (hydrogenation) gives the keyintermediate, pyrrolidine-ester 9. Reaction of pyrrolidine 9 withchloroformate 10

where R⁶ is any of the R³ groups except H) provides thepyrrolidine-carbamate ester 11. Deprotection of the ester 11 thenfurnishes the cis-substituted pyrrolidine-carbamate acids I of theinvention.

Scheme 3 shows the synthesis of other analogs from the key intermediatepyrrolidine-ester 9. Palladium-mediated reaction of 9 with aryl orheteroaryl bromides (e.g. method of Buchwald et. al., J. Am. Chem. Soc.,2001, 123, 7727) furnishes the N-aryl or N-heteroaryl pyrrolidine acidsII of the invention. Reductive amination of 9 (e.g. the procedure ofAbdel-Magid et al, J. Org. Chem. 1996, 61, 3849) with appropriatealdehydes R^(3a)CHO provides the substituted alkyl pyrrolidine acids IIIof the invention. Treatment of 9 with diverse acid chlorides R^(3a)COClin the presence of an appropriate base gives the corresponding amidepyrrolidine acids IV of the invention. Reaction of 9 with diverseisocyanate R^(3a)N═C═O provides the corresponding urea pyrrolidine acidsV of the invention. Treatment of 9 with sulfonyl chlorides R^(3b)SO₂Clfurnishes the corresponding sulfonamide pyrrolidine acids VI of theinvention. It is understood that these representative reactions ofpyrrolidine 9 shown in Scheme 3 are also readily applied to thesubsequent key secondary amine intermediates described below to give thecorresponding functionalized analogs.

A synthesis of the homologated cis-substituted pyrrolidine acids VII ofthe invention is shown in Scheme 4. Treatment of aldehyde 3 with asubstituted alkynylmetal agent (generated from alkyne 12 in the presenceof an appropriate base, e.g. n-butyllithium) furnishes the acetylenicalcohol adduct 13. Alcohol 13 is deoxygenated under standard methods(e.g. Et₃SiH/CF₃CO₂H; e.g. J. Org. Chem., 1990, 55, 555) to give thealkynoate ester 14. The alkynoate ester 14 undergoes selective reductionby standard methods (e.g. H₂/Lindlar's catalyst) to give the Z-alkenylester 15. This Z-alkenyl unsaturated ester 15 is then reacted withN-trimethylsilylmethyl N-methoxymethyl benzylamine 7 under standardliterature conditions (J. S. Carey, J. Org. Chem., 2001, 66, 2526-2529)to give the corresponding N-benzyl pyrrolidine-ester 16. Deprotection ofthe N-benzyl group (hydrogenation) gives the key intermediate,pyrrolidine-ester 17. Reaction of pyrrolidine 17 with chloroformate 10provides pyrrolidine-carbamate ester 18. Deprotection of the ester 18then provides the cis-substituted pyrrolidine-carbamate acids VII of theinvention.

An alternative synthesis of the key intermediate pyrrolidine ester 17(for the special case where m=0) is shown in Scheme 4A. Alcohol 13 isacetylated under standard conditions to give the acetylenic acetate 13A,which is then reacted with N-trimethylsilylmethyl N-methoxymethylbenzylamine 7 under standard literature conditions (e.g. J. S. Carey, J.Org. Chem., 2001, 66, 2526-2529) to give the N-benzyl dihydropyrrole16A. Exhaustive hydrogenation/hydrogenolysis of the benzylic acetate,the dihydropyrrole and the N-benzyl group then provides the intermediatepyrrolidine-ester 17.

Scheme 5 illustrates a synthetic route to the correspondingtrans-substituted pyrrolidine-carbamate acids VIII of the invention.Aldehyde 3 undergoes a Wittig reaction with a phosphoranylidene ester 19(e.g. “Preparation of Alkenes, A Practical Approach”, J. M. J. Williams,Ed., Chapter 2, “The Wittig reaction and related methods”, N.J.Lawrence, Oxford University Press, 1996) to give the predominantlyE-alkenyl ester 20. The E-alkenyl ester 15 is then reacted withN-trimethylsilylmethyl N-methoxymethyl benzylamine 7 under standardliterature conditions (J. S. Carey, J. Org. Chem. 2001, 66, 2526-2529)to give the corresponding trans-substituted N-benzyl pyrrolidine-ester21. Deprotection of the N-benzyl group (hydrogenation) gives the keyintermediate, pyrrolidine-ester 22. Reaction of pyrrolidine 22 withchloroformate 10 provides pyrrolidine-carbamate ester 23. Deprotectionof the ester 23 then provides the cis-substituted pyrrolidine-carbamateacids VIII of the invention.

Two alternative synthetic routes to the series of correspondingdihydropyrrole acids V of the invention are shown in Schemes 6-8. Thefirst sequence (Schemes 6 and 7) begins with the acetylation of thehydroxy-acetylenic ester 13 to provide acetylenic acetate 24. Dipolarcycloaddition with the N-trimethylsilylmethyl N-methoxymethyl4-methoxybenzylamine 25 (prepared as for compound 7 except using4-methoxybenzylamine instead of benzylamine; J. S. Carey, J. Org. Chem.2001, 66, 2526-2529) furnishes the corresponding dihydropyrrole-ester26. Deoxygenation of the allylic acetate 26 (e.g. (Ph₃P)₂PdCl₂-mediated;Tsuji, J., et al, Synthesis, 1986, 623-727) provide two isomeric alkeneproducts: the β,γ unsaturated ester 27 and the dihydropyrrole ester 28.Deprotection of the 4-methoxybenzylamine (e.g. Yang, B. V., Synlett,1993, 195-196) subsequently furnish the corresponding key amine-esterintermediates 29 and 30 respectively. Reaction of dihydropyrroles 29 and30 with chloroformate 10 provide the pyrrolidine-carbamate esters 31 and32 respectively. Deprotection of the esters 31 and 32 then give thedihydropyrrole-carbamate acids IX and X of the invention.

An alternative synthetic sequence (for substrates where deoxygenation of13 occurs readily to provide 14), involves the reaction of 14 withN-trimethylsilylmethyl N-methoxymethyl 4-methoxybenzylamine 25 (as forScheme 6) to furnish the corresponding dihydropyrrole-ester 30 directly(shown in Scheme 8). The rest of the synthetic route to providecarbamate acids X of the invention is then identical to that shown inScheme 5.

The synthesis of dihydropyrrole carbamate-acid analogs XI is shown inScheme 9. Alkylation of a halogenated phenol or hydroxy-heteroarene 32with mesylate 4 in the presence of base provides the haloarene 33.Coupling of 33 with silyl-alkyne 34 under standard Sonogashiraconditions (ref. Organocopper Reagents, a Practical Approach, R. J. K.Taylor, Ed., Chapter 10, pp 217-236, Campbell, I. B., Oxford UniversityPress, 1994) provides the arylalkyne 35. Removal of the silyl group(e.g. fluoride) followed by treatment with base and an appropriatechloroformate 36 (e.g. methyl chloroformate) furnishes the alkynoateester 37. Dipolar cycloaddition with N-trimethylsilylmethylN-methoxymethyl 4-methoxybenzylamine 25 furnishes the correspondingdihydropyrrole-ester 38. Deprotection of the N-methoxybenzyl amine groupis achieved under standard conditions to furnish the dihydropyrroleester 39. This intermediate then is reacted with electrophiles (e.g.chloroformate 10 in the presence of base) to provide carbamates 40. Itis understood that reaction of 39 with other electrophiles (analogous tothe examples in Scheme 3) can also be similarly achieved.Carbamate-esters 40 are then deprotected to furnish carbamate acids XIof the invention.

The synthesis of homologated dihydropyrrole acid XII is shown in Scheme10. Dihydropyrrole ester 39 is suitably protected (e.g. PG₂ as thet-butyloxy carbamate or as the benzyloxy carbamate) as intermediate 41.Dihydropyrrole ester 41 is reduced by standard literature methods (e.g.diisobutylaluminum hydride) to give the allylic alcohol 42. Halogenationby standard literature methods (e.g. Ph₃P/CBr₄ or PBr₃ to furnish thebromide; Ph₃P/CCl₄ to furnish the chloride) furnishes the correspondingallylic halide 43. Carbonylation (ref. Kiji, J. et al, Bull. Chem. Soc.Jpn., 1996, 69, 1029-1031) with carbon monoxide in the presence of aruthenium catalyst and methanol) of 43 furnishes the dihydropyrroleester 44. Deprotection of 44 furnishes dihydropyrrole 45, whichundergoes reaction with chloroformate 10 to give carbamate ester 46.Deprotection of carbamate ester 46 then furnishes dihydropyrrole acidsXII of the invention.

The synthesis of cis-3,4-disubstituted pyrrolidine acids XIII is shownin Scheme 11. Protected dihydropyrrole ester 41 is hydrogenated tofurnish the protected cis-3,4-disubstituted pyrrolidine ester 47.Deprotection of the amine gives the pyrrolidine ester 48, which thenundergoes reaction with chloroformate 10 to provide the pyrrolidinecarbamate ester 49. Deprotection of esters 49 furnishes pyrrolidinecarbamate-acids XIII of the invention.

The synthesis of homologated cis-3,4-disubstituted pyrrolidine acids XIVis shown in Scheme 12. Hydrogenation of intermediate dihydropyrroleester 44 furnishes the cis-3,4-disubstituted pyrrolidine ester 50, whichis then deprotected to provide pyrrolidine-ester 51. Reaction ofpyrrolidine 51 with chloroformate 10 furnishes the correspondingpyrrolidine carbamate-ester 52, which is then deprotected to provide thecis-3,4-disubstituted pyrrolidine acids XIV of the invention.

An alternative synthesis of homologated pyrrolidine acids XIV is shownin Scheme 13. The pyrrolidine ester 47 is deprotected to give acid 53.Acid 53 is homologated under a standard Arndt-Eistert protocol (ref. E.Gordon et al., J. Med. Chem., 1988, 31, 2199), which first involvesconversion to diazoketone 54 under standard conditions (isobutylchloroformate followed by diazomethane). Treatment of diazoketone 54with a silver salt (e.g. silver benzoate) in the presence of methanolprovides the homologated pyrrolidine ester 50. Deprotection ofpyrrolidine 50 followed by reaction with chloroformate 10 furnishes thecarbamate ester 52, which is then deprotected to give homologatedpyrrolidine acids XIV of the invention.

The synthesis of ether-containing analogs XV and XVI are shown inSchemes 14-15. In Scheme 14, treatment of the aldehyde 55 with theHorner-Emmons reagent 5 (W. C. Still et al., Tetrahedron Lett. 1985, 24,4405-5508) provides the Z-alkenyl ester 56. This Z-alkenyl ester 56 isthen reacted with N-trimethylsilylmethyl N-methoxymethyl benzylamine 7under standard literature conditions (e.g. J. S. Carey, J. Org. Chem.,2001, 66, 2526-2529) to give the corresponding N-benzylpyrrolidine-ester 57. Reaction of halo-arene 57 with an appropriatemetallating agent (e.g. isopropyl magnesium bromide, reference: P.Knochel et al., Synthesis, 2002, 565-569) furnishes the correspondingarylmagnesium reagent, which is then reacted with formaldehyde toprovide aryl alcohol 58. Treatment of alcohol 58 with mesylate 4 in thepresence of base provides the corresponding ether 59, which is thendeprotected to give the pyrrolidine ester 60. Reaction of pyrrolidine 60with chloroformate 10 provides carbamate ester 61, which is thendeprotected to furnish the ether-acids XV of the invention.

In Scheme 15, treatment of the haloaryl pyrrolidine ester 57 aryl withan appropriate vinyl tin reagent (e.g. tributylvinyltin) under Stillecoupling conditions (reference: Farina, V., Krishnamurthy, V., andScott, W. J., Organic Reactions, 1997, 50, 1) provides the correspondingvinyl intermediate, which can then undergo hydroboration (e.g.borane-THF) to give the alcohol 62. Treatment of alcohol 62 withmesylate 4 in the presence of base provides the corresponding ether 63,which is then deprotected to furnish pyrrolidine 64. Reaction ofpyrrolidine 64 with chloroformate 10 provides carbamate ester 65, whichis then deprotected to furnish the ether-pyrrolidine acids XVI of theinvention.

The synthesis of carbon-linked analogs XVII is shown in Scheme 16. Thehalo-aryl pyrrolidine ester 57 is reacted with an appropriate heteroaryl(R⁵)-substituted acetylene 66 in the presence of an appropriatepalladium catalyst (e.g. (Ph₃P)₂PdCl₂) and a copper (I) salt (e.g. CuI)in a Sonogashira coupling reaction (ref: Organocopper Reagents, aPractical Approach, R. J. K. Taylor, Ed., Chapter 10, pp 217-236,Campbell, I. B., Oxford University Press, 1994) to furnish thearylacetylene 67. The arylacetylene ester 67 is hydrogenated to providethe corresponding pyrrolidine ester 68. Reaction of pyrrolidine 68 withchloroformate 10 provides carbamate ester 69, which is then deprotectedto furnish the alkylaryl pyrrolidine acids XVII of the invention.

The synthesis of piperidine acid analogs XVIII is shown in Scheme 17.Metallation of a halo-arene 70 (e.g. isopropyl magnesium bromide,reference: P. Knochel et al., Synthesis, 2002, 565-569, ormagnesium/anthracene, ref.) provides the corresponding organomagnesiumreagent 71, which is reacted with an appropriate pyridine ester 72 inthe presence of a suitable chloroformate 10 and a copper (I) salt (e.g.CuBr.SMe₂) to give the corresponding dihydropyridine carbamate ester 73(e.g. ref. D. J. Wallace et al., Synthesis, 2001, 1784-1789). Reductionof the dihydropyridine esters 73 (e.g. hydrogenation) furnishespiperidine carbamate ester 74, which is then deprotected to give thephenol 75. Reaction of phenol 75 with mesylate 4 in the presence of baseprovides the piperidine carbamate ester 76, which is then deprotected tofurnish pyrrolidine carbamate acids XVIII of the invention.

The synthesis of tetrahydropyridine acids XIX is shown in Scheme 18. Anappropriately protected piperidone 77 is reacted with aldehyde 78 in thepresence of base (standard aldol reaction) followed by deoxygenation tofurnish the 2-alkyl piperidone 79. Treatment of 79 with triflicanhydride in the presence of base (e.g. iPr₂NMg) under thermodynamicconditions furnishes enol triflate 80. Palladium-mediated carbonylationunder standard literature conditions (e.g. S. K. Thompson et al., J.Org. Chem., 1990, 55, 3004) with carbon monoxide in the presence of analcohol (preferably methanol) furnishes the tetrahydropyridine ester 81.Deprotection of 81 provides phenol 82, which is alkylated with mesylate4 to give the tetrahydropyridine ester 83. Deprotection of 83, followedby reaction with chloroformate 10, furnishes tetrahydropyridinecarbamate ester 84. Deprotection of carbamate ester 84 givetetrahydropyridine carbamate-acids XIX of the invention.

The synthesis of cis 3,4-disubstituted piperidine acids XX is shown inScheme 19. Tetrahydropyridine ester 83 is reduced (hydrogenation) togive the cis 3,4-disubstituted piperidine ester 85. Deprotection of thepiperidine 85, followed by reaction with chloroformate 10, providespiperidine carbamate ester 86. Deprotection of carbamate ester 86provides cis 3,4-disubstituted piperidine carbamate-acids XX of theinvention.

The synthesis of piperazine acids XXI (where in Formula I q=1, Z is abond, p=2 and E is nitrogen) is shown in Schemes 20A and 20B. In Scheme20A reductive amination of aldehyde 78 with a readily availablemonoprotected piperazine ester 87 furnishes the alkylated piperazineester 88. Deprotection of 88 provides the phenol 89, which is alkylatedwith mesylate 4 in the presence of base to furnish the alkylatedpiperazine ester 90. Selective deprotection of the amine followed byreaction with chloroformates 10 provides piperazine carbamate-esters 91.Deprotection of carbamate-esters 91 furnishes piperazine carbamate-acidsXXI of the invention.

Alternatively, piperazine carbamate-acids XXI can also be synthesizedaccording to the synthetic sequences shown in Scheme 20B. Reductiveamination of the monoprotected piperazine ester 87 with aldehyde 3directly provides the key intermediate alkylated piperazine ester 90. Asdescribed for Scheme 20A, a 3-step sequence involving: 1) selectivedeprotection of the amine functionality of 90; 2) reaction withchloroformates 10 and 3) deprotection of the acid, furnishes piperazinecarbamate-acids XXI of the invention. In addition, complete deprotectionof piperazine-ester 90 provides piperazine acid 92, which is thenreacted with chloroformates 10 to furnish piperazine carbamate-acids XXIof the invention.

The synthesis of azetidine-acids XXII (in Formula I where Z is a bond,q=0, p=1 and E=CH) is shown in Scheme 21. The hydroxyaryl ester 93 isalkylated with mesylate 4 under basic conditions, then deprotected toprovide the acid 94. Acid 94 is converted to the corresponding acidchloride under standard conditions (oxalyl chloride in the presence of acatalytic amount of dimethyl formamide), then is treated with abis-imine such as 95 under Staudinger conditions (reference: R. M.Adlington et. al., J. Med. Chem., 2001, 44, 1491) to furnish the keyintermediate β-lactam aldehyde 96. Protection of the aldehyde 96 (e.g.as the dimethyl acetal) followed by reduction of the resulting β-lactamacetal (e.g. AlH₂Cl, reference: B. Alcaide et. al. J. Org. Chem., 1999,64, 9596) furnishes the corresponding azetidine acetal 97. Deprotectionof the azetidine under standard conditions (e.g. ceric ammonium nitrate)followed by reaction with chloroformates 10 furnishes the correspondingazetidine-carbamates. Deprotection of the aldehyde under standardconditions (aqueous acid) followed by a standard oxidation of thealdehyde (e.g. NaClO₂/H₂NSO₃H; reference: B. O. Lindgren et. al., ActaChem. Scand., 1973, 27, 888 or E. Dalcanale et. al., J. Org. Chem.,1986, 51, 567) provides the azetidine carbamate-acids XXII of theinvention.

Direct oxidation of the intermediate β-lactam aldehyde 96 (e.g. theLindgren oxidation) furnishes the azetidinone acids XXIII of theinvention.

A general method for synthesis of the cis-disubstituted β-lactam acidsXXIV and the corresponding trans-disubstituted azetidinone-acids XXV isdepicted in Scheme 22. A suitably protected carboxylic acid 98 (e.g.,PG₁=benzyl) is converted to the acid chloride 99, which upon treatmentwith a suitably substituted bis-imine (e.g. 95) undergoes a Staudingerreaction (reference: R. M. Adlington et. al., J. Med. Chem., 2001, 44,1491) to furnish the key intermediate β-lactam aldehyde 100. Oxidationof aldehyde 100 to the corresponding carboxylic acid (e.g. Lindgrenoxidation) followed by protection (esterification) provides the β-lactamester 101. Removal of the N-4-methoxyphenyl group provides thecorresponding deprotected β-lactam ester 102, which then is reacted witha variety of diverse aryl boronic acids 103

where R⁸ is H, alkyl, alkoxy, halogen, amino or substituted amino, andX₁ is CH or N) under copper-mediated catalysis (Chan, D. M. T. et al.Tetrahedron Lett. 1998, 39, 2933; Evans, D. A. et al. Tetrahedron Lett.1998, 39, 2937) to provide the corresponding N-aryl esters 104.Deprotection of the phenol followed by alkylation of the phenol withmesylate 4 under basic conditions provides the alkylated β-lactam ester105. Appropriate deprotection of the β-lactam ester 105 gives a mixtureof the cis-disubstituted azetidinone acids XXIV and the epimerizedtrans-disubstituted azetidinone acids XXV of the invention.

An alternative synthesis of azetidinone acids XXIII is illustrated inScheme 23. Deprotection of the phenol moiety of azetidinone-ester 101provides the phenol 102, which undergoes base-mediated alkylation usingmesylate 4 to give the alkylated phenol azetidinone-ester 107. Removalof the final protecting group provides the azetidinone acids XXIII. Yetanother route to acids XXIII is shown in Scheme 24). The β-lactamaldehyde intermediate 100 is reduced by standard methods (e.g. NaBH₄),after which the phenol is deprotected to give the phenol-azetidinonealcohol 108. Alkylation of 108 with mesylate 4 provides the alkylatedphenol azetidinone alcohol 109, which is then oxidized under standardliterature conditions (e.g. Jones reagent) to give the azetidinone acidsXXIII of the invention.

It should be noted that in Schemes 21-24, a number of the racemicintermediates (e.g. 102 and 107) as well as the final productazetidinone-acids XXIII-XXV, are amenable to separation into theirindividual enantiomers by chiral preparative HPLC.

An approach to the direct asymmetric synthesis of the key chiralazetidinone intermediate 112 is shown in Scheme 25. A chiralligand-mediated coupling of the acid chloride 99 with suitably protectedcarboxy-tosyl imines such as 110 (Ref: Taggi, A. E. et al. J. Am. Chem.Soc. 2002, 124, 6626) affords the chiral cis-disubstituted β-lactam 111with high enantioselectivity. N-deprotection of the tosylated β-lactam111 furnishes the corresponding β-lactam, which then is reacted withdiverse aryl boronic acids 103 under copper-mediated catalysis (Chan, D.M. T. et al. Tetrahedron Lett. 1998, 39, 2933; Evans, D. A. et al.Tetrahedron Lett. 1998, 39, 2937) to provide the corresponding N-arylesters 112. The chiral intermediate 112 can be processed as before tofurnish chiral azetidinone-acids XXIII-XXV of the invention as describedin Schemes 21-24 and 26.

An alternative approach to N-carbamate azetidine acids XXII is shown inScheme 26. Reduction of the azetidinone-aldehyde intermediate 100 (e.g.with chloroalane) provides the N-aryl azetidine alcohol 113.Deprotection of the N-aryl azetidine to the corresponding azetidinefollowed by reaction with appropriate chloroformates 10 affords theN-carbamate azetidine alcohols 114. Oxidation of azetidine alcohol 114to the acid (e.g. Jones reagent) followed by protection of the acid(esterification) provides the azetidine carbamate ester 115.Deprotection of 115 gives the free phenol 116, which undergoesbase-mediated reaction with mesylate 4 to give the alkylated azetidinecarbamate ester 117. Finally, deprotection of 117 provides the desiredcarbamate acids XXII of the invention.

The synthesis of the corresponding N-Aryl azetidine acids XXVI is shownin Scheme 27. Reduction of either racemic N-aryl azetidinone ester 104or chiral N-aryl azetidinone ester 112 (e.g. chloroalane) provides thecorresponding azetidine-alcohol 118. Deprotection of the phenol of 118followed by alkylation with mesylate 4 and finally oxidation (e.g. Jonesreagent) provides the N-aryl azetidine acids XXVI of the invention.

The azetidinone acids XXVII and the pyrrolidinone acids XXVIII may beobtained following the general procedure shown in Scheme 28 (literatureprecedent: Wee, A. G. H.; Liu, B-S.; Zhang, L. J. Org. Chem., 1992,57(16), 4404; also Wee, A. G. H.; Liu, B. Tetrahedron Lett. 1996, 37(2),145-148). The intermediate aniline 121 can be synthesized either by: a)reductive amination (e.g. with NaBH(OAc)₃) of aldehyde 3 with anappropriate aniline or b) an aniline carbamate 119 can be alkylated withan alkyl halide 120 in the presence of a base (e.g. NaH) and then thecarbamate can be removed with a nucleophilic base (e.g. KOH). Acylationof aniline 121 with the malonyl acid chloride 122 in the presence ofbase (e.g. Et₃N or pyridine or DMAP) provides the malonyl amide 123.Treatment of the β-ketoamide 123 with an appropriate diazotization agent(e.g. methanesulfonyl azide) in the presence of base (e.g. DBU) providesthe diazoester 124. Rhodium-mediated intramolecular cyclization (by C—Hinsertion) of diazo-ester 124 provides a mixture of the correspondingazetidinone and pyrrolidinone esters. Deprotection of these estersprovides the azetidinone acids XXVII of the invention as a mixture ofdiastereomers (cis and trans) and the pyrrolidinone acids XXVIII as amixture of diastereomers (cis and trans) of the invention. The ratio ofproducts XXVII and XXVIII can be controlled by an appropriate choice ofthe substituent on the aniline moiety.

An alternative synthesis of piperidine carbamate-acids XIX andpiperidine N-aryl acids XXIX is shown in Scheme 29. Treatment of anappropriately protected aryl substituted halide 70 with activated zincprovides the aryl zinc reagent 125 (ref: Rieke, R., et al., J. Org.Chem., 1991, 56, 1445-1453). An appropriately protected piperidone ester126 is converted to the corresponding enol nonaflate 127 under standardliterature conditions (ref: Bellina, F. et al, Tetrahedron, 1999, 55,2103-2112). Treatment of enol nonaflate 127 with the aryl zinc reagent125 in the presence of a palladium catalyst (ref: Bellina, F. et al,Tetrahedron, 1999, 55, 2103-2112) provides the coupled α,β-unsaturatedester 81. The phenol of 81 is deprotected and alkylated with mesylate 4(as for Scheme 18) to provide the piperidine ester 83. Hydrogenation andN-deprotection of 83 furnishes the key piperidine ester 128, which isthen converted according to the sequence in Scheme 19 to the piperidinecarbamate acids XX of the invention.

As shown in Scheme 30, the intermediate piperidine ester 128 can also bereacted with aryl or heteroaryl halides in the presence of a palladiumcatalyst (e.g. method of Buchwald et. al., J. Am. Chem. Soc., 2001, 123,7727) to furnish the N-aryl or N-heteroaryl piperidine acids XXIX of theinvention. Alternatively, intermediate piperidine ester 128 can also bereacted directly with electron-deficient heteroaryl halides in thepresence of base to give N-heteroaryl piperidine acids XXX of theinvention.

Scheme 31 shows the synthesis of the α,β-unsaturated piperidine acids.The phenol moiety of the N-protected piperidine ester 81 is deprotectedand alkylated with mesylate 4 to provide alkylated phenol 83, which isthen deprotected to furnish the key free piperidine intermediate 129.Intermediate 129 is treated with an appropriate chloroformate 10 anddeprotected to give piperidine carbamate-acids XIX of the invention (asfor Scheme 18). Alternatively, piperidine 129 can be treated with anaryl halide or a heteroaryl halide in the presence of a palladiumcatalyst (e.g. method of Buchwald et. al., J. Am. Chem. Soc., 2001, 123,7727) followed by deprotection of the acid to furnish the N-aryl orN-heteroaryl piperidine acids XXXI and XXXII of the invention. Inaddition, electron-deficient heteroaryl halides can be directly reactedwith piperidine intermediate 129 in the presence of base followed bydeprotection of the acid to provide N-heteroaryl piperidine acids XXXIIof the invention.

The synthesis of β,γ-unsaturated piperidine acids XXXIII-XXXV of theinvention is shown in Scheme 32. The piperidine α,β-unsaturated esterintermediate 129 is reacted with a chloroformate 10 to provide thecorresponding piperidine carbamate α,β-unsaturated ester 130.Base-mediated deprotection of the acid (ester hydrolysis) furnished thepiperidine carbamate β,γ-unsaturated acids XXXIII of the invention.Similarly, reaction of piperidine 129 with aryl halides in the presenceof a palladium catalyst (as for Scheme 31) provided the correspondingN-aryl piperidine β,γ-unsaturated ester, which upon base hydrolysisfurnished the N-aryl piperidine β,γ-unsaturated acids XXXIV of theinvention. Reaction of piperidine 129 with 1-deficient heteroarylhalides in the presence of base provided the corresponding N-heteroarylpiperidine α,β-unsaturated ester, which upon base hydrolysis furnishedthe N-heteroaryl piperidine β,γ-unsaturated acids XXXV of the invention.

The preparation of pyrrolidinone acids XXXVI of the invention is shownin Scheme 33. A suitably protected pyrrolidinone ester 130 isdeprotonated with an appropriate base (e.g. lithium diisopropylamide)and alkylated with a protected aryl halide 70 to furnish the alkylatedpyrrolidinone ester 131. The phenol of pyrrolidinone ester 131 isdeprotected and alkylated with mesylate 4 to provide pyrrolidinone ester132, which is N-deprotected to give the key pyrrolidinone esterintermediate 133. Palladium-mediated arylation with an appropriatearylboronic acid followed by deprotection of the acid providespyrrolidinone acids XXXVI of the invention.

The preparation of pyrrolidinone acids XXXVII and XXXIX of the inventionis shown in Scheme 34. The appropriately protected pyrrolidinone ester134 is deprotonated with an appropriate base (e.g. lithiumdiisopropylamide) and alkylated with halide 70 to provide the alkylatedlactam ester 135 (ref: Saksena, A. K., et al., Patent PCT WO0208256;August, R. A., J. Chem. Soc. Perkin 1, 1996, 507-514). Deprotection ofthe phenol moiety of 135 followed by alkylation with mesylate 4 in thepresence of base gives the alkylated phenol lactam ester 136.N-Deprotection of the lactam provides the key intermediate lactam 137,which is reacted with appropriate aryl boronic acids to provide thecorresponding N-aryl lactam ester followed by deprotection of the acidto provide N-aryl pyrrolidinone acids XXXVII of the invention.Alternatively, after lactam 137 is reacted with aryl boronic acids toprovide the corresponding N-aryl lactam ester, the lactam is reduced(e.g. 2 step sequence: a) LiBHEt₃, b) Et₃SiH/BFOEt₂; ref: Ezquerra, J.,J. Org. Chem., 1995, 60, 2925-2930) to the corresponding pyrrolidineester, which is then deprotected to give the N-aryl pyrrolidine acidsXXXIX of the invention.

The preparation of N-substituted pyrrolidine acids XXXVIII-XXXX of theinvention is shown in Scheme 35. The lactam ester 136 is reduced (e.g. 2step sequence: a) LiBHEt₃, b) Et₃SiH/BFOEt₂) to the correspondingpyrrolidine ester, which then undergoes N-deprotection to provide thekey intermediate pyrrolidine ester 139. Reaction of pyrrolidine 139 withchloroformates 10 provide the carbamate pyrrolidine ester 140, which isthen deprotected to furnish carbamate pyrrolidine acids XXXVIII of theinvention. Reaction of pyrrolidine 139 with aryl halides in the presenceof a palladium catalyst (as for Scheme 31) provided the correspondingN-aryl pyrrolidine ester, which upon deprotection of the acid furnishedthe N-aryl pyrrolidine acids XXXIX of the invention. Reaction ofpyrrolidine 139 with 1-deficient heteroaryl halides in the presence ofbase or under palladium catalysis provided the correspondingN-heteroaryl pyrrolidine ester, which upon deprotection of the acidfurnished the N-heteroaryl pyrrolidine acids XXXX of the invention.

The synthesis of pyrrolidine acids XLI-XLIII of the invention is shownin Scheme 36. The benzamide-protected α-amino ester 141 is alkylatedwith mesylate 4 in the presence of base to furnish the alkylated phenol142. Reduction of the benzamide and ester (e.g. LiAlH₄ or LiBH₄)followed by Michael reaction of the resultant amine with acrylonitrilein the presence of base to give the β-amino-nitrile 143. Chlorination ofthe alcohol 143 (e.g. with SOCl₂) followed by base (e.g.NaN(TMS)₂)-mediated intramolecular cyclization provides thecyano-pyrrolidine 144. This sequence is precedented in the literature(R. Achini, Helv. Chim. Acta, 1981, 64, 2203-2218). Acid-mediatedhydrolysis (e.g. H₂SO₄) of the nitrile in the presence of an appropriatealcohol provides the corresponding pyrrolidine ester, which isdebenzylated (e.g. hydrogenation) to provide the key pyrrolidine esterintermediate 145. Reaction of pyrrolidine 145 with chloroformates 10provide the corresponding carbamate pyrrolidine ester, which is thendeprotected to furnish carbamate pyrrolidine acids XLI of the invention.Reaction of pyrrolidine 145 with aryl halides in the presence of apalladium catalyst (as for Scheme 31) provided the corresponding N-arylpyrrolidine ester, which upon deprotection of the acid furnished theN-aryl pyrrolidine acids XLII of the invention. Reaction of pyrrolidine145 with π-deficient heteroaryl halides in the presence of base or underpalladium catalysis provided the corresponding N-heteroaryl pyrrolidineester, which upon deprotection of the acid furnished the N-heteroarylpyrrolidine acids XLIII of the invention.

An asymmetric synthesis of pyrrolidine acids XLIV and XLV is shown inScheme 37. The maleimide 146 is reacted with N-trimethylsilylmethylN-methoxymethyl benzylamine 7 under standard literature conditions (e.g.J. S. Carey, J. Org. Chem., 2001, 66, 2526-2529) to give thecorresponding N-benzyl pyrrolidine-ester 147. The imide 147 is thenreacted with an appropriately protected aryl Grignard reagent 148; theintermediate hydroxy lactam is reduced (e.g. NaBH₄) andthermally-induced intramolecular cyclization provides the lactone 149.Deprotection of the phenol moiety of lactone 149 followed bybase-mediated alkylation of the phenol with mesylate 4 provides thealkoxyphenol lactone 150. Deprotection (hydrogenation) of the N-benzylgroup with concomitant hydrogenolysis of the benzylic lactone C—O bondprovides the pyrrolidine acid 151, which is reprotected with anappropriate alcohol to furnish the key intermediate pyrrolidine ester152. Reaction of 152 with an appropriate chloroformate 10 and aciddeprotection (as for Scheme 4) provides chiral pyrrolidine carbamateacids XLIV of the invention. Reaction of 152 with appropriate arylhalides or heteroaryl halides followed by acid deprotection (as forScheme 35) provides chiral N-aryl pyrrolidine acids XLV and chiralN-heteroaryl pyrrolidine acids XLVI of the invention respectively.

The synthesis of hydantoin acids XLVII of the invention is shown inScheme 38. Reductive amination (e.g. NaBH(OAc)₃ or NaBH₃CN) of arylaldehyde 3 with an aspartate derivative 153 gives the amino-diester 154.Reaction of amino-diester 154 with appropriate aryl isocyanates 155 withheat results in the formation of hydantoin ester 156. Deprotection ofhydantoin ester 156 provides hydantoin acids XLVII of the invention. Itshould be noted that the use of L- or S-aspartate diesters provides theindividual enantiomers of hydantoin acids XLVII of the invention.

The synthesis of piperidine acids XLVIII-L of the invention is shown inScheme 39. Reaction of the α-carboalkoxy piperidone 157 with nonaflylfluoride in the presence of base provides the enol nonaflate 158.Palladium mediated coupling of enol nonaflate 158 with the organozincreagent 125 (as previously described for Scheme 29; ref: (Bellina, F. etal, Tetrahedron, 1999, 55, 2103-2112)) provides the coupledα,β-unsaturated ester 159. The phenol of 159 is deprotected andalkylated with mesylate 4 (as for Scheme 18) to provide the piperidineester 160. N-deprotection of 160 furnishes the key piperidine ester 161,which is then converted according to the sequence in Scheme 37 to thepiperidine carbamate acids XLVIII of the invention, the N-arylpiperidine acids XLIX of the invention and N-heteroaryl piperidine acidsL of the invention.

The preparation of piperidine acids L1-LIII of the invention is shown inScheme 40. Treatment of α-carboalkoxy piperidone 157 with triflicanhydride in the presence of base provides enol triflate 162.Palladium-mediated coupling of enol triflate 162 to an appropriatelysubstituted aryl boronic acid 163 (ref: Wustrow, D. J. and Wise, L. D.,Synthesis, 1991, 993-995) provides the coupled piperidine α,βunsaturated ester 164. Deprotection of the phenol moiety of 164 followedby alkylation with mesylate 4 provides the alkoxy phenol piperidineester 165, which is then N-deprotected to furnish the free piperidineester 166.

Piperidine ester 166 is then converted according to the sequences shownin Scheme 37 to the piperidine carbamate acids LI of the invention, theN-aryl piperidine acids LII of the invention and N-heteroaryl piperidineacids LIII of the invention.

Scheme 41 illustrates the synthesis of piperidine acids LIV-LVI of theinvention. Reduction (hydrogenation) of the α,β unsaturated ester 166provides the corresponding piperidine ester 167. Piperidine ester 167 isthen converted according to the sequences shown in Scheme 37 to thepiperidine carbamate acids LIV of the invention, the N-aryl piperidineacids LV of the invention and N-heteroaryl piperidine acids LVI of theinvention.

In this and the following Reaction Schemes,

In the above schemes, it will be seen that PG is a protecting group fora carboxylic acid. PG₂ is a protecting group for an amine. PG₃ is aprotecting group for a phenol.

Unless otherwise indicated, the term “lower alkyl”, “alkyl” or “alk” asemployed herein alone or as part of another group includes both straightand branched chain hydrocarbons, containing 1 to 20 carbons, preferably1 to 10 carbons, more preferably 1 to 8 carbons, in the normal chain,and may optionally include an oxygen or nitrogen in the normal chain,such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl,pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl,2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the variousbranched chain isomers thereof, and the like as well as such groupsincluding 1 to 4 substituents such as halo, for example F, Br, Cl or Ior CF₃, alkoxy, aryl, aryloxy, aryl(aryl) or diaryl, arylalkyl,arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy,amino, hydroxy, hydroxyalkyl, acyl, heteroaryl, heteroaryloxy,cycloheteroalkyl, arylheteroaryl, arylalkoxycarbonyl, heteroarylalkyl,heteroarylalkoxy, aryloxyalkyl, aryloxyaryl, alkylamido, alkanoylamino,arylcarbonylamino, nitro, cyano, thiol, haloalkyl, trihaloalkyl and/oralkylthio and/or any of the R³ groups.

Unless otherwise indicated, the term “cycloalkyl” as employed hereinalone or as part of another group includes saturated or partiallyunsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groupscontaining 1 to 3 rings, including monocyclicalkyl, bicyclicalkyl andtricyclicalkyl, containing a total of 3 to 20 carbons forming the rings,preferably 3 to 10 carbons, forming the ring and which may be fused to 1or 2 aromatic rings as described for aryl, which include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyland cyclododecyl, cyclohexenyl,

any of which groups may be optionally substituted with 1 to 4substituents such as halogen, alkyl, alkoxy, hydroxy, aryl, aryloxy,arylalkyl, cycloalkyl, alkylamido, alkanoylamino, oxo, acyl,arylcarbonylamino, amino, nitro, cyano, thiol and/or alkylthio and/orany of the substituents for alkyl.

The term “cycloalkenyl” as employed herein alone or as part of anothergroup refers to cyclic hydrocarbons containing 3 to 12 carbons,preferably 5 to 10 carbons and 1 or 2 double bonds. Exemplarycycloalkenyl groups include cyclopentenyl, cyclohexenyl, cycloheptenyl,cyclooctenyl, cyclohexadienyl, and cycloheptadienyl, which may beoptionally substituted as defined for cycloalkyl.

The term “cycloalkylene” as employed herein refers to a “cycloalkyl”group which includes free bonds and thus is a linking group such as

and the like, and may optionally be substituted as defined above for“cycloalkyl”.

The term “alkanoyl” as used herein alone or as part of another grouprefers to alkyl linked to a carbonyl group.

Unless otherwise indicated, the term “lower alkenyl” or “alkenyl” asused herein by itself or as part of another group refers to straight orbranched chain radicals of 2 to 20 carbons, preferably 2 to 12 carbons,and more preferably 1 to 8 carbons in the normal chain, which includeone to six double bonds in the normal chain, and may optionally includean oxygen or nitrogen in the normal chain, such as vinyl, 2-propenyl,3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl,2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl,3-undecenyl, 4-dodecenyl, 4,8,12-tetradecatrienyl, and the like, andwhich may be optionally substituted with 1 to 4 substituents, namely,halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl,cycloalkyl, amino, hydroxy, heteroaryl, cycloheteroalkyl, alkanoylamino,alkylamido, arylcarbonylamino, nitro, cyano, thiol, alkylthio and/or anyof the substituents for alkyl set out herein.

Unless otherwise indicated, the term “lower alkynyl” or “alkynyl” asused herein by itself or as part of another group refers to straight orbranched chain radicals of 2 to 20 carbons, preferably 2 to 12 carbonsand more preferably 2 to 8 carbons in the normal chain, which includeone triple bond in the normal chain, and may optionally include anoxygen or nitrogen in the normal chain, such as 2-propynyl, 3-butynyl,2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl,3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl, 3-undecynyl,4-dodecynyl and the like, and which may be optionally substituted with 1to 4 substituents, namely, halogen, haloalkyl, alkyl, alkoxy, alkenyl,alkynyl, aryl, arylalkyl, cycloalkyl, amino, heteroaryl,cycloheteroalkyl, hydroxy, alkanoylamino, alkylamido, arylcarbonylamino,nitro, cyano, thiol, and/or alkylthio, and/or any of the substituentsfor alkyl set out herein.

The terms “arylalkenyl” and “arylalkynyl” as used alone or as part ofanother group refer to alkenyl and alkynyl groups as described abovehaving an aryl substituent.

Where alkyl groups as defined above have single bonds for attachment toother groups at two different carbon atoms, they are termed “alkylene”groups and may optionally be substituted as defined above for “alkyl”.

Where alkenyl groups as defined above and alkynyl groups as definedabove, respectively, have single bonds for attachment at two differentcarbon atoms, they are termed “alkenylene groups” and “alkynylenegroups”, respectively, and may optionally be substituted as definedabove for “alkenyl” and “alkynyl”.

(CH₂)_(x), (CH₂)_(x) ¹, (CH₂)_(x) ², (CH₂)_(x) ³, (CH₂)_(x) ⁴,(CH₂)_(m), (CH₂)_(n), (CH₂)_(p) and (CH₂)_(q) includes alkylene,allenyl, alkenylene or alkynylene groups, as defined herein, each ofwhich may optionally include an oxygen or nitrogen in the normal chain(in addition to the number of carbon atoms as defined by x¹, x², x³, x⁴,m, n, p and q) which may optionally include 1, 2, or 3 substituentswhich include alkyl, alkenyl, halogen, cyano, hydroxy, alkoxy, amino,thioalkyl, keto, C₃-C₆ cycloalkyl, alkylcarbonylamino oralkylcarbonyloxy; the alkyl substituent may be an alkylene moiety of 1to 4 carbons which may be attached to one or two carbons in the(CH₂)_(x), (CH₂)_(x) ¹, (CH₂)_(x) ², (CH₂)_(x) ³, (CH₂)_(x) ⁴, (CH₂)_(x)⁵, (CH₂)_(x) ⁶, (CH₂)_(x) ⁷, (CH₂)_(x) ⁸, (CH₂)_(m), (CH₂)_(n),(CH₂)_(p), or (CH₂)_(q) group to form a cycloalkyl group therewith.

Examples of (CH₂)_(x), (CH₂)_(x) ¹, (CH₂)_(x) ², (CH₂)_(x) ³, (CH₂)_(x)⁴, CH₂)_(x) ⁵, (CH₂)_(x) ⁶, (CH₂)_(x) ⁷, (CH₂)_(x) ⁸, (CH₂)_(m),(CH₂)_(n), (CH₂)_(p), (CH₂)_(q), alkylene, alkenylene and alkynyleneinclude

The term “halogen” or “halo” as used herein alone or as part of anothergroup refers to chlorine, bromine, fluorine, and iodine as well as CF₃,with chlorine or fluorine being preferred.

The term “metal ion” refers to alkali metal ions such as sodium,potassium or lithium and alkaline earth metal ions such as magnesium andcalcium, as well as zinc and aluminum.

Unless otherwise indicated, the term “aryl” or the group

where Q is C, as employed herein alone or as part of another grouprefers to monocyclic and bicyclic aromatic groups containing 6 to 10carbons in the ring portion (such as phenyl or naphthyl including1-naphthyl and 2-naphthyl) and may optionally include one to threeadditional rings fused to a carbocyclic ring or a heterocyclic ring(such as aryl, cycloalkyl, heteroaryl or cycloheteroalkyl rings forexample

and may be optionally substituted through available carbon atoms with 1,2, or 3 groups selected from hydrogen, halo, haloalkyl, alkyl,haloalkyl, alkoxy, haloalkoxy, alkenyl, trifluoromethyl,trifluoromethoxy, alkynyl, cycloalkyl-alkyl, cycloheteroalkyl,cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, aryloxy,aryloxyalkyl, arylalkoxy, alkoxycarbonyl, arylcarbonyl, arylalkenyl,aminocarbonylaryl, arylthio, arylsulfinyl, arylazo, heteroarylalkyl,heteroarylalkenyl, heteroarylheteroaryl, heteroaryloxy, hydroxy, nitro,cyano, amino, substituted amino wherein the amino includes 1 or 2substituents (which are alkyl, aryl or any of the other aryl compoundsmentioned in the definitions), thiol, alkylthio, arylthio,heteroarylthio, arylthioalkyl, alkoxyarylthio, alkylcarbonyl,arylcarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl,aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino,arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonylamino orarylsulfonaminocarbonyl and/or any of the substituents for alkyl set outherein.

Unless otherwise indicated, the term “lower alkoxy”, “alkoxy”, “aryloxy”or “aralkoxy” as employed herein alone or as part of another groupincludes any of the above alkyl, aralkyl or aryl groups linked to anoxygen atom.

Unless otherwise indicated, the term “substituted amino” as employedherein alone or as part of another group refers to amino substitutedwith one or two substituents, which may be the same or different, suchas alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl,haloalkyl, hydroxyalkyl, alkoxyalkyl or thioalkyl. These substituentsmay be further substituted with a carboxylic acid and/or any of thesubstituents for alkyl as set out above. In addition, the aminosubstituents may be taken together with the nitrogen atom to which theyare attached to form 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl,4-morpholinyl, 4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-1-piperazinyl,4-arylalkyl-1-piperazinyl, 4-diarylalkyl-1-piperazinyl, 1-pyrrolidinyl,1-piperidinyl, or 1-azepinyl, optionally substituted with alkyl, alkoxy,alkylthio, halo, trifluoromethyl or hydroxy.

Unless otherwise indicated, the term “lower alkylthio”, alkylthio”,“arylthio” or “aralkylthio” as employed herein alone or as part ofanother group includes any of the above alkyl, aralkyl or aryl groupslinked to a sulfur atom.

Unless otherwise indicated, the term “lower alkylamino”, “alkylamino”,“arylamino”, or “arylalkylamino” as employed herein alone or as part ofanother group includes any of the above alkyl, aryl or arylalkyl groupslinked to a nitrogen atom.

Unless otherwise indicated, the term “acyl” as employed herein by itselfor part of another group, as defined herein, refers to an organicradical linked to a carbonyl

group; examples of acyl groups include any of the R³ groups attached toa carbonyl, such as alkanoyl, alkenoyl, aroyl, aralkanoyl, heteroaroyl,cycloalkanoyl, cycloheteroalkanoyl and the like.

Unless otherwise indicated, the term “cycloheteroalkyl” as used hereinalone or as part of another group refers to a 5-, 6- or 7-memberedsaturated or partially unsaturated ring which includes 1 to 2 heteroatoms such as nitrogen, oxygen and/or sulfur, linked through a carbonatom or a heteroatom, where possible, optionally via the linker(CH₂)_(p) (where p is 1, 2 or 3), such as

and the like. The above groups may include 1 to 4 substituents such asalkyl, halo, oxo and/or any of the substituents for alkyl or aryl setout herein. In addition, any of the cycloheteroalkyl rings can be fusedto a cycloalkyl, aryl, heteroaryl or cycloheteroalkyl ring.

Unless otherwise indicated, the term “heteroaryl” as used herein aloneor as part of another group refers to a 5- or 6-membered aromatic ringincluding

where Q is N, which includes 1, 2, 3 or 4 hetero atoms such as nitrogen,oxygen or sulfur, and such rings fused to an aryl, cycloalkyl,heteroaryl or cycloheteroalkyl ring (e.g. benzothiophenyl, indolyl), andincludes possible N-oxides. The heteroaryl group may optionally include1 to 4 substituents such as any of the substituents for alkyl or arylset out above. Examples of heteroaryl groups include the following:

and the like.

The term “cycloheteroalkylalkyl” as used herein alone or as part ofanother group refers to cycloheteroalkyl groups as defined above linkedthrough a C atom or heteroatom to a (CH₂)_(p) chain.

The term “heteroarylalkyl” or “heteroarylalkenyl” as used herein aloneor as part of another group refers to a heteroaryl group as definedabove linked through a C atom or heteroatom to a —(CH₂)_(p)— chain,alkylene or alkenylene as defined above.

The term “polyhaloalkyl” as used herein refers to an “alkyl” group asdefined above which includes from 2 to 9, preferably from 2 to 5, halosubstituents, such as F or Cl, preferably F, such as CF₃CH₂, CF₃ orCF₃CF₂CH₂.

The term “polyhaloalkyloxy” as used herein refers to an “alkoxy” or“alkyloxy” group as defined above which includes from 2 to 9, preferablyfrom 2 to 5, halo substituents, such as F or Cl, preferably F, such asCF₃CH₂O, CF₃O or CF₃CF₂CH₂O.

The term “prodrug esters” as employed herein includes prodrug esterswhich are known in the art for carboxylic and phosphorus acid esterssuch as methyl, ethyl, benzyl and the like. Other prodrug ester examplesof R⁴ include the following groups: (1-alkanoyloxy)alkyl such as,

wherein R^(a), R^(b) and R^(c) are H, alkyl, aryl or arylalkyl; however,R^(a)O cannot be HO.Examples of such prodrug esters R⁴ include

Other examples of suitable prodrug esters R⁴ include

wherein R^(a) can be H, alkyl (such as methyl or t-butyl), arylalkyl(such as benzyl) or aryl (such as phenyl); R^(d) is H, alkyl, halogen oralkoxy, R^(e) is alkyl, aryl, arylalkyl or alkoxyl, and n₁ is 0, 1 or 2.

Where the compounds of structure I are in acid form they may form apharmaceutically acceptable salt such as alkali metal salts such aslithium, sodium or potassium, alkaline earth metal salts such as calciumor magnesium as well as zinc or aluminum and other cations such asammonium, choline, diethanolamine, lysine (D or L), ethylenediamine,t-butylamine, t-octylamine, tris-(hydroxymethyl)aminomethane (TRIS),N-methyl glucosamine (NMG), triethanolamine and dehydroabietylamine.

All stereoisomers of the compounds of the instant invention arecontemplated, either in admixture or in pure or substantially pure form.The compounds of the present invention can have asymmetric centers atany of the carbon atoms including any one or the R substituents.Consequently, compounds of formula I can exist in enantiomeric ordiastereomeric forms or in mixtures thereof. The processes forpreparation can utilize racemates, enantiomers or diastereomers asstarting materials. When diastereomeric or enantiomeric products areprepared, they can be separated by conventional methods for example,chromatographic or fractional crystallization.

Where desired, the compounds of structure I may be used in combinationwith one or more hypolipidemic agents or lipid-lowering agents and/orone or more other types of therapeutic agents including antidiabeticagents, anti-obesity agents, antihypertensive agents, plateletaggregation inhibitors, and/or anti-osteoporosis agents, which may beadministered orally in the same dosage form, in a separate oral dosageform or by injection.

Where desired, the compounds of structure I may be used in combinationwith one or more hypolipidemic agents or lipid-lowering agents and/orone or more other types of therapeutic agents including antidiabeticagents, anti-obesity agents, antihypertensive agents, plateletaggregation inhibitors, and/or anti-osteoporosis agents, which may beadministered orally in the same dosage form, in a separate oral dosageform or by injection.

The hypolipidemic agent or lipid-lowering agent which may be optionallyemployed in combination with the compounds of formula I of the inventionmay include 1,2,3 or more MTP inhibitors, HMG CoA reductase inhibitors,squalene synthetase inhibitors, fibric acid derivatives, ACATinhibitors, lipoxygenase inhibitors, cholesterol absorption inhibitors,ileal Na⁺/bile acid cotransporter inhibitors, upregulators of LDLreceptor activity, bile acid sequestrants, and/or nicotinic acid andderivatives thereof.

MTP inhibitors employed herein include MTP inhibitors disclosed in U.S.Pat. No. 5,595,872, U.S. Pat. No. 5,739,135, U.S. Pat. No. 5,712,279,U.S. Pat. No. 5,760,246, U.S. Pat. No. 5,827,875, U.S. Pat. No.5,885,983 and U.S. application Ser. No. 09/175,180 filed Oct. 20, 1998,now U.S. Pat. No. 5,962,440. Preferred are each of the preferred MTPinhibitors disclosed in each of the above patents and applications.

All of the above U.S. patents and applications are incorporated hereinby reference.

Most preferred MTP inhibitors to be employed in accordance with thepresent invention include preferred MTP inhibitors as set out in U.S.Pat. Nos. 5,739,135 and 5,712,279, and U.S. Pat. No. 5,760,246.

The most preferred MTP inhibitor is9-[4-[4-[[2-(2,2,2-Trifluoroethoxy)benzoyl]amino]-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide

The hypolipidemic agent may be an HMG CoA reductase inhibitor whichincludes, but is not limited to, mevastatin and related compounds asdisclosed in U.S. Pat. No. 3,983,140, lovastatin (mevinolin) and relatedcompounds as disclosed in U.S. Pat. No. 4,231,938, pravastatin andrelated compounds such as disclosed in U.S. Pat. No. 4,346,227,simvastatin and related compounds as disclosed in U.S. Pat. Nos.4,448,784 and 4,450,171. Other HMG CoA reductase inhibitors which may beemployed herein include, but are not limited to, fluvastatin, disclosedin U.S. Pat. No. 5,354,772, atorvastatin disclosed in U.S. Pat. Nos.4,681,893, 5,273,995, 5,385,929 and 5,686,104, itavastatin(Nissan/Sankyo's nisvastatin (NK-104)) disclosed in U.S. Pat. No.5,011,930, Shionogi-Astra/Zeneca visastatin (ZD-4522) disclosed in U.S.Pat. No. 5,260,440, and related statin compounds disclosed in U.S. Pat.No. 5,753,675, pyrazole analogs of mevalonolactone derivatives asdisclosed in U.S. Pat. No. 4,613,610, indene analogs of mevalonolactonederivatives as disclosed in PCT application WO 86/03488,6-[2-(substituted-pyrrol-1-yl)-alkyl)pyran-2-ones and derivativesthereof as disclosed in U.S. Pat. No. 4,647,576, Searle's SC-45355 (a3-substituted pentanedioic acid derivative) dichloroacetate, imidazoleanalogs of mevalonolactone as disclosed in PCT application WO 86/07054,3-carboxy-2-hydroxy-propane-phosphonic acid derivatives as disclosed inFrench Patent No. 2,596,393, 2,3-disubstituted pyrrole, furan andthiophene derivatives as disclosed in European Patent Application No.0221025, naphthyl analogs of mevalonolactone as disclosed in U.S. Pat.No. 4,686,237, octahydronaphthalenes such as disclosed in U.S. Pat. No.4,499,289, keto analogs of mevinolin (lovastatin) as disclosed inEuropean Patent Application No. 0,142,146 A2, and quinoline and pyridinederivatives disclosed in U.S. Pat. Nos. 5,506,219 and 5,691,322.

In addition, phosphinic acid compounds useful in inhibiting HMG CoAreductase suitable for use herein are disclosed in GB 2205837.

The squalene synthetase inhibitors suitable for use herein include, butare not limited to, α-phosphono-sulfonates disclosed in U.S. Pat. No.5,712,396, those disclosed by Biller et al, J. Med. Chem., 1988, Vol.31, No. 10, pp 1869-1871, including isoprenoid(phosphinylmethyl)phosphonates as well as other known squalenesynthetase inhibitors, for example, as disclosed in U.S. Pat. Nos.4,871,721 and 4,924,024 and in Biller, S. A., Neuenschwander, K.,Ponpipom, M. M., and Poulter, C. D., Current Pharmaceutical Design, 2,1-40 (1996).

In addition, other squalene synthetase inhibitors suitable for useherein include the terpenoid pyrophosphates disclosed by P. Ortiz deMontellano et al, J. Med. Chem., 1977, 20, 243-249, the farnesyldiphosphate analog A and presqualene pyrophosphate (PSQ-PP) analogs asdisclosed by Corey and Volante, J. Am. Chem. Soc., 1976, 98, 1291-1293,phosphinylphosphonates reported by McClard, R. W. et al, J.A.C.S., 1987,109, 5544 and cyclopropanes reported by Capson, T. L., PhD dissertation,June, 1987, Dept. Med. Chem. U of Utah, Abstract, Table of Contents, pp16, 17, 40-43, 48-51, Summary.

Other hypolipidemic agents suitable for use herein include, but are notlimited to, fibric acid derivatives, such as fenofibrate, gemfibrozil,clofibrate, bezafibrate, ciprofibrate, clinofibrate and the like,probucol, and related compounds as disclosed in U.S. Pat. No. 3,674,836,probucol and gemfibrozil being preferred, bile acid sequestrants such ascholestyramine, colestipol and DEAE-Sephadex (Secholex®, Policexide®)and cholestagel (Sankyo/Geltex), as well as lipostabil (Rhone-Poulenc),Eisai E-5050 (an N-substituted ethanolamine derivative), imanixil(HOE-402), tetrahydrolipstatin (THL), istigmastanylphosphorylcholine(SPC, Roche), aminocyclodextrin (Tanabe Seiyoku), Ajinomoto AJ-814(azulene derivative), melinamide (Sumitomo), Sandoz 58-035, AmericanCyanamid CL-277,082 and CL-283,546 (disubstituted urea derivatives),nicotinic acid (niacin), acipimox, acifran, neomycin, p-aminosalicylicacid, aspirin, poly(diallylmethylamine) derivatives such as disclosed inU.S. Pat. No. 4,759,923, quaternary amine poly(diallyldimethylammoniumchloride) and ionenes such as disclosed in U.S. Pat. No. 4,027,009, andother known serum cholesterol lowering agents.

The hypolipidemic agent may be an ACAT inhibitor such as disclosed in,Drugs of the Future 24, 9-15 (1999), (Avasimibe); “The ACAT inhibitor,Cl-1011 is effective in the prevention and regression of aortic fattystreak area in hamsters”, Nicolosi et al, Atherosclerosis (Shannon,Irel). (1998), 137(1), 77-85; “The pharmacological profile of FCE 27677:a novel ACAT inhibitor with potent hypolipidemic activity mediated byselective suppression of the hepatic secretion of ApoB100-containinglipoprotein”, Ghiselli, Giancarlo, Cardiovasc. Drug Rev. (1998), 16(1),16-30; “RP 73163: a bioavailable alkylsulfinyl-diphenylimidazole ACATinhibitor”, Smith, C., et al, Bioorg. Med. Chem. Lett. (1996), 6(1),47-50; “ACAT inhibitors: physiologic mechanisms for hypolipidemic andanti-atherosclerotic activities in experimental animals”, Krause et al,Editor(s): Ruffolo, Robert R., Jr.; Hollinger, Mannfred A.,Inflammation: Mediators Pathways (1995), 173-98, Publisher: CRC, BocaRaton, Fla.; “ACAT inhibitors: potential anti-atherosclerotic agents”,Sliskovic et al, Curr. Med. Chem. (1994), 1(3), 204-25; “Inhibitors ofacyl-CoA:cholesterol O-acyl transferase (ACAT) as hypocholesterolemicagents. 6. The first water-soluble ACAT inhibitor with lipid-regulatingactivity. Inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). 7.Development of a series of substitutedN-phenyl-N′-[(1-phenylcyclopentyl)methyl]ureas with enhancedhypocholesterolemic activity”, Stout et al, Chemtracts: Org. Chem.(1995), 8(6), 359-62, or TS-962 (Taisho Pharmaceutical Co. Ltd) as wellas F-1394, CS-505, F-12511, HL-004, K-10085 and YIC-C8-434.

The hypolipidemic agent may be an upregulator of LDL receptor activitysuch as MD-700 (Taisho Pharmaceutical Co. Ltd) and LY295427 (Eli Lilly).

The hypolipidemic agent may be a cholesterol absorption inhibitorpreferably Schering-Plough's SCH48461 (ezetimibe) as well as thosedisclosed in Atherosclerosis 115, 45-63 (1995) and J. Med. Chem. 41, 973(1998).

The hypolipidemic agent may be an ileal Na⁺/bile acid cotransporterinhibitor such as disclosed in Drugs of the Future, 24, 425-430 (1999).

The lipid-modulating agent may be a cholesteryl ester transfer protein(CETP) inhibitor such as Pfizer's CP 529,414 as well as those disclosedin WO/0038722 (i.e. (torcetrapib) and in EP 818448 (Bayer) and EP 992496and Pharmacia's SC-744 and SC-795, as well as CETi-1 and JTT-705.

The ATP citrate lyase inhibitor which may be employed in the combinationof the invention may include, for example, those disclosed in U.S. Pat.No. 5,447,954.

The other lipid agent also includes a phytoestrogen compound such asdisclosed in WO 00/30665 including isolated soy bean protein, soyprotein concentrate or soy flour as well as an isoflavone such asgenistein, daidzein, glycitein or equol, or phytosterols, phytostanol ortocotrienol as disclosed in WO 2000/015201; a beta-lactam cholesterolabsorption inhibitor such as disclosed in EP 675714; an HDL upregulatorsuch as an LXR agonist, a PPAR alpha agonist and/or an FXR agonist; aPPAR delta agonist (e.g. GW-501516, ref: Oliver, Jr., W. R., et. al,Proc. Nat. Acad. Sci. USA, 2001, 98, 5306-5311), an LDL catabolismpromoter such as disclosed in EP 1022272; a sodium-proton exchangeinhibitor such as disclosed in DE 19622222; an LDL-receptor inducer or asteroidal glycoside such as disclosed in U.S. Pat. No. 5,698,527 and GB2304106; an anti-oxidant such as beta-carotene, ascorbic acid,α-tocopherol or retinol as disclosed in WO 94/15592 as well as Vitamin Cand an antihomocysteine agent such as folic acid, a folate, Vitamin B6,Vitamin B12 and Vitamin E; isoniazid as disclosed in WO 97/35576; acholesterol absorption inhibitor, an HMG-CoA synthase inhibitor, or alanosterol demethylase inhibitor as disclosed in WO 97/48701; a PPAR δagonist for treating dyslipidemia; or a sterol regulating elementbinding protein-I (SREBP-1) as disclosed in WO 2000/050574, for example,a sphingolipid, such as ceramide, or neutral sphingomyelenase (N-SMase)or fragment thereof.

The above-mentioned U.S. patents are incorporated herein by reference.The amounts and dosages employed will be as indicated in the Physician'sDesk Reference and/or in the patents set out above.

The compounds of formula I of the invention will be employed in a weightratio to the hypolipidemic agent (were present), within the range fromabout 500:1 to about 1:500, preferably from about 100:1 to about 1:100.

The dose administered must be carefully adjusted according to age,weight and condition of the patient, as well as the route ofadministration, dosage form and regimen and the desired result.

The dosages and formulations for the hypolipidemic agent will be asdisclosed in the various patents and applications discussed above.

The dosages and formulations for the other hypolipidemic agent to beemployed, where applicable, will be as set out in the latest edition ofthe Physicians' Desk Reference.

For oral administration, a satisfactory result may be obtained employingthe MTP inhibitor in an amount within the range of from about 0.01 mg toabout 500 mg and preferably from about 0.1 mg to about 100 mg, one tofour times daily.

A preferred oral dosage form, such as tablets or capsules, will containthe MTP inhibitor in an amount of from about 1 to about 500 mg,preferably from about 2 to about 400 mg, and more preferably from about5 to about 250 mg, one to four times daily.

For oral administration, a satisfactory result may be obtained employingan HMG CoA reductase inhibitor, for example, pravastatin, lovastatin,simvastatin, atorvastatin, fluvastatin or rosuvastatin in dosagesemployed as indicated in the Physician's Desk Reference, such as in anamount within the range of from about 1 to 2000 mg, and preferably fromabout 4 to about 200 mg.

The squalene synthetase inhibitor may be employed in dosages in anamount within the range of from about 10 mg to about 2000 mg andpreferably from about 25 mg to about 200 mg.

A preferred oral dosage form, such as tablets or capsules, will containthe HMG CoA reductase inhibitor in an amount from about 0.1 to about 100mg, preferably from about 0.5 to about 80 mg, and more preferably fromabout 1 to about 40 mg.

A preferred oral dosage form, such as tablets or capsules will containthe squalene synthetase inhibitor in an amount of from about 10 to about500 mg, preferably from about 25 to about 200 mg.

The hypolipidemic agent may also be a lipoxygenase inhibitor including a15-lipoxygenase (15-LO) inhibitor such as benzimidazole derivatives asdisclosed in WO 97/12615, 15-LO inhibitors as disclosed in WO 97/12613,isothiazolones as disclosed in WO 96/38144, and 15-LO inhibitors asdisclosed by Sendobry et al “Attenuation of diet-induced atherosclerosisin rabbits with a highly selective 15-lipoxygenase inhibitor lackingsignificant antioxidant properties”, Brit. J. Pharmacology (1997) 120,1199-1206, and Cornicelli et al, “15-Lipoxygenase and its Inhibition: ANovel Therapeutic Target for Vascular Disease”, Current PharmaceuticalDesign, 1999, 5, 11-20.

The compounds of formula I and the hypolipidemic agent may be employedtogether in the same oral dosage form or in separate oral dosage formstaken at the same time.

The compositions described above may be administered in the dosage formsas described above in single or divided doses of one to four timesdaily. It may be advisable to start a patient on a low dose combinationand work up gradually to a high dose combination.

The preferred hypolipidemic agent is pravastatin, simvastatin,lovastatin, atorvastatin, fluvastatin or rosuvastatin as well as niacinand/or cholestagel.

The other antidiabetic agent which may be optionally employed incombination with the compound of formula I may be 1, 2, 3 or moreantidiabetic agents or antihyperglycemic agents including insulinsecretagogues or insulin sensitizers, or other antidiabetic agentspreferably having a mechanism of action different from the compounds offormula I of the invention, which may include biguanides, sulfonylureas, glucosidase inhibitors, PPARγ agonists such asthiazolidinediones, PPARα agonists such as fibric acid derivatives,PPARδ agonists or antagonists, PPARα/γ dual agonists, aP2 inhibitors,dipeptidyl peptidase IV (DP4) inhibitors, SGLT2 inhibitors, glycogenphosphorylase inhibitors, glucagon-like peptide-1 (GLP-1), PTP-1B(protein tyrosine phosphatase-1B) inhibitors, 11β-HSD 1(11β-hydroxy-steroid dehydrogenase 1) inhibitors and/or meglitinides, aswell as insulin.

The other antidiabetic agent may be an oral antihyperglycemic agentpreferably a biguanide such as metformin or phenformin or salts thereof,preferably metformin HCl.

Where the antidiabetic agent is a biguanide, the compounds of structureI will be employed in a weight ratio to biguanide within the range fromabout 0.001:1 to about 10:1, preferably from about 0.01:1 to about 5:1.

The other antidiabetic agent may also preferably be a sulfonyl urea suchas glyburide (also known as glibenclamide), glimepiride (disclosed inU.S. Pat. No. 4,379,785), glipizide, gliclazide or chlorpropamide, otherknown sulfonylureas or other antihyperglycemic agents which act on theATP-dependent channel of the β-cells, with glyburide and glipizide beingpreferred, which may be administered in the same or in separate oraldosage forms.

The compounds of structure I will be employed in a weight ratio to thesulfonyl urea in the range from about 0.01:1 to about 100:1, preferablyfrom about 0.02:1 to about 5:1.

The oral antidiabetic agent may also be a glucosidase inhibitor such asacarbose (disclosed in U.S. Pat. No. 4,904,769) or miglitol (disclosedin U.S. Pat. No. 4,639,436), which may be administered in the same or ina separate oral dosage forms.

The compounds of structure I will be employed in a weight ratio to theglucosidase inhibitor within the range from about 0.01:1 to about 100:1,preferably from about 0.05:1 to about 10:1.

The compounds of structure I may be employed in combination with a PPARγ agonist such as a thiazolidinedione oral anti-diabetic agent or otherinsulin sensitizers (which has an insulin sensitivity effect in NIDDMpatients) such as rosiglitazone (Glaxo SmithKline), pioglitazone(Takeda), Mitsubishi's MCC-555 (disclosed in U.S. Pat. No. 5,594,016),Glaxo-Welcome's GL-262570, englitazone (CP-68722, Pfizer) ordarglitazone (CP-86325, Pfizer, isaglitazone (MIT/J&J), JTT-501(JPNT/P&U), L-895645 (Merck), R-119702 (Sankyo/WL), N,N-2344 orbalaglitazone (Dr. Reddy/NN), or YM-440 (Yamanouchi), preferablyrosiglitazone and pioglitazone.

The compounds of structure I will be employed in a weight ratio to thethiazolidinedione in an amount within the range from about 0.01:1 toabout 100:1, preferably from about 0.05 to about 10:1.

The sulfonyl urea and thiazolidinedione in amounts of less than about150 mg oral antidiabetic agent may be incorporated in a single tabletwith the compounds of structure I.

The compounds of structure I may also be employed in combination with aantihyperglycemic agent such as insulin or with glucagon-like peptide-1(GLP-1) such as GLP-1 (1-36) amide, GLP-1 (7-36) amide, GLP-1 (7-37) (asdisclosed in U.S. Pat. No. 5,614,492 to Habener, the disclosure of whichis incorporated herein by reference), as well as AC2993 (Amylin) andLY-315902 (Lilly), which may be administered via injection, intranasal,inhalation or by transdermal or buccal devices.

Where present, metformin, the sulfonyl ureas, such as glyburide,glimepiride, glipyride, glipizide, chlorpropamide and gliclazide and theglucosidase inhibitors acarbose or miglitol or insulin (injectable,pulmonary, buccal, or oral) may be employed in formulations as describedabove and in amounts and dosing as indicated in the Physician's DeskReference (PDR).

Where present, metformin or salt thereof may be employed in amountswithin the range from about 500 to about 2000 mg per day which may beadministered in single or divided doses one to four times daily.

Where present, the thiazolidinedione anti-diabetic agent may be employedin amounts within the range from about 0.01 to about 2000 mg/day whichmay be administered in single or divided doses one to four times perday.

Where present insulin may be employed in formulations, amounts anddosing as indicated by the Physician's Desk Reference.

Where present GLP-1 peptides may be administered in oral buccalformulations, by nasal administration or parenterally as described inU.S. Pat. No. 5,346,701 (TheraTech), U.S. Pat. Nos. 5,614,492 and5,631,224 which are incorporated herein by reference.

The other antidiabetic agent may also be a PPAR α/γ dual agonist such asAZ-242/tesaglitazar (Astra/Zeneca; as described: in B. Ljung et. al., J.Lipid Res., 2002, 43, 1855-1863), GW-409544 (Glaxo-Wellcome),KRP-297/MK-767 (Kyorin/Merck; as described in: K. Yajima et. al., Am. J.Physiol. Endocrinol. Metab., 2003, 284: E966-E971) as well as thosedisclosed by Murakami et al, “A Novel Insulin Sensitizer Acts As aColigand for Peroxisome Proliferation-Activated Receptor Alpha (PPARalpha) and PPAR gamma. Effect on PPAR alpha Activation on Abnormal LipidMetabolism in Liver of Zucker Fatty Rats”, Diabetes 47, 1841-1847 (1998)or the compounds (from Bristol-Myers Squibb) described in U.S. Pat. No.6,414,002.

The antidiabetic agent may be an SGLT2 inhibitor such as disclosed inU.S. provisional application No. 60/158,773, filed Oct. 12, 1999(attorney file LA49), employing dosages as set out therein. Preferredare the compounds designated as preferred in the above application.

The antidiabetic agent may be an aP2 inhibitor such as disclosed in U.S.application Ser. No. 09/391,053, filed Sep. 7, 1999, and in U.S.provisional application No. 60/127,745, filed Apr. 5, 1999 (attorneyfile LA27*), employing dosages as set out herein. Preferred are thecompounds designated as preferred in the above application.

The antidiabetic agent may be a DP4 (Dipeptidyl peptidase IV) inhibitorsuch as disclosed in Provisional Application 60/188,555 filed Mar. 10,2000 (attorney file LA50), WO99/38501, WO99/46272, WO99/67279(PROBIODRUG), WO99/67278 (PROBIODRUG), WO99/61431 (PROBIODRUG),NVP-DPP728A(1-[[[2-[(5-cyanopyridin-2-yl)amino]ethyl]amino]acetyl]-2-cyano-(S)-pyrrolidine)(Novartis) (preferred) as disclosed by Hughes et al, Biochemistry,38(36), 11597-11603, 1999, TSL-225(tryptophyl-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid (disclosedby Yamada et al, Bioorg. & Med. Chem. Lett. 8 (1998) 1537-1540,2-cyanopyrrolidides and 4-cyanopyrrolidides as disclosed by Ashworth etal, Bioorg. & Med. Chem. Lett., Vol. 6, No. 22, pp 1163-1166 and2745-2748 (1996) employing dosages as set out in the above references.

The meglitinide which may optionally be employed in combination with thecompound of formula I of the invention may be repaglinide, nateglinide(Novartis) or KAD1229 (PF/Kissei), with repaglinide being preferred.

The compound of formula I will be employed in a weight ratio to themeglitinide, PPAR γ agonist, PPAR α/γ dual agonist, aP2 inhibitor, DP4inhibitor or SGLT2 inhibitor within the range from about 0.01:1 to about100:1, preferably from about 0.05 to about 10:1.

The other type of therapeutic agent which may be optionally employedwith a compound of formula I may be 1, 2, 3 or more of an anti-obesityagent including a melanocortin receptor (MC4R) agonist, amelanin-concentrating hormone receptor (MCHR) antagonist, a growthhormone secretagogue receptor (GHSR) antagonist, an orexin receptorantagonist, a CCK (cholecystokinin) agonist, a GLP-1 agonists, NPY1 orNPY5 antagonist, a corticotropin releasing factor (CRF) antagonist, ahistamine receptor-3 (H3) modulator, a PPARγ modulator, a PPARδmodulator, a beta 3 adrenergic agonist, a lipase inhibitor, a serotonin(and dopamine) reuptake inhibitor, a erotonin receptor agonist (e.g.BVT-933), an aP2 inhibitor, a thyroid receptor agonist and/or ananorectic agent.

The beta 3 adrenergic agonist which may be optionally employed incombination with a compound of formula I may be AJ9677(Takeda/Dainippon), L750355 (Merck), or CP331648 (Pfizer) or other knownbeta 3 agonists as disclosed in U.S. Pat. Nos. 5,541,204, 5,770,615,5,491,134, 5,776,983 and 5,488,064, with AJ9677, L750,355 and CP331648being preferred.

The lipase inhibitor which may be optionally employed in combinationwith a compound of formula I may be orlistat or ATL-962 (Alizyme), withorlistat being preferred.

The serotonin (and dopoamine) reuptake inhibitor which may be optionallyemployed in combination with a compound of formula I may be sibutramine,topiramate (Johnson & Johnson) or CNTF/axokine (Regeneron), withsibutramine and topiramate being preferred.

The thyroid receptor agonist which may be optionally employed incombination with a compound of formula I may be a thyroid receptorligand as disclosed in WO97/21993 (U. Cal SF), WO99/00353 (KaroBio),GB98/284425 (KaroBio), and U.S. Provisional Application 60/183,223 filedFeb. 17, 2000, with compounds of the KaroBio applications and the aboveU.S. provisional application being preferred.

The anorectic agent which may be optionally employed in combination witha compound of formula I may be fenfluramine, dexfenfluramine,fluxoxamine, fluoxetine, paroxetine, sertraline, chlorphentermine,clorofex, clortermine, picilorex, sibutramine, dexamphetamine,phentermine, phenylpropanolamine or mazindol. Other anorectic agentswhich may be optionally employed in combination with a compound offormula I include CNTF (ciliary neurotrophic factor)/Axokine(Regeneron), BDNF (brain-derived neurotrophic factor), leptin orcannabinoid receptor antagonists, such as SR-141716/rimonabant (Sanofi)or SLV-319 (Solvay).

The various anti-obesity agents described above may be employed in thesame dosage form with the compound of formula I or in different dosageforms, in dosages and regimens as generally known in the art or in thePDR.

The antihypertensive agents which may be employed in combination withthe compound of formula I of the invention include ACE inhibitors,angiotensin II receptor antagonists, NEP/ACE inhibitors, as well ascalcium channel blockers, β-adrenergic blockers and other types ofantihypertensive agents including diuretics.

The angiotensin converting enzyme inhibitor which may be employed hereinincludes those containing a mercapto (—S—) moiety such as substitutedproline derivatives, such as any of those disclosed in U.S. Pat. No.4,046,889 to Ondetti et al mentioned above, with captopril, that is,1-[(2S)-3-mercapto-2-methylpropionyl]-L-proline, being preferred, andmercaptoacyl derivatives of substituted prolines such as any of thosedisclosed in U.S. Pat. No. 4,316,906 with zofenopril being preferred.

Other examples of mercapto containing ACE inhibitors that may beemployed herein include rentiapril (fentiapril, Santen) disclosed inClin. Exp. Pharmacol. Physiol. 10:131 (1983); as well as pivopril andYS980.

Other examples of angiotensin converting enzyme inhibitors which may beemployed herein include any of those disclosed in U.S. Pat. No.4,374,829 mentioned above, withN-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline, that is,enalapril, being preferred, any of the phosphonate substituted amino orimino acids or salts disclosed in U.S. Pat. No. 4,452,790 with(S)-1-[6-amino-2-[[hydroxy-(4-phenylbutyl)phosphinyl]oxy]-1-oxohexyl]-L-prolineor (ceronapril) being preferred, phosphinylalkanoyl prolines disclosedin U.S. Pat. No. 4,168,267 mentioned above with fosinopril beingpreferred, any of the phosphinylalkanoyl substituted prolines disclosedin U.S. Pat. No. 4,337,201, and the phosphonamidates disclosed in U.S.Pat. No. 4,432,971 discussed above.

Other examples of ACE inhibitors that may be employed herein includeBeecham's BRL 36,378 as disclosed in European Patent Application Nos.80822 and 60668; Chugai's MC-838 disclosed in C.A. 102:72588v and Jap.J. Pharmacol. 40:373 (1986); Ciba-Geigy's CGS 14824(3-([1-ethoxycarbonyl-3-phenyl-(1S)-propyl]amino)-2,3,4,5-tetrahydro-2-oxo-1-(3S)-benzazepine-1acetic acid HCl) disclosed in U.K. Patent No. 2103614 and CGS 16,617(3(S)-[[(1S)-5-amino-1-carboxypentyl]amino]-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-ethanoicacid) disclosed in U.S. Pat. No. 4,473,575; cetapril (alacepril,Dainippon) disclosed in Eur. Therap. Res. 39:671 (1986); 40:543 (1986);ramipril (Hoechsst) disclosed in Euro. Patent No. 79-022 and Curr. Ther.Res. 40:74 (1986); Ru 44570 (Hoechst) disclosed in Arzneimittelforschung34:1254 (1985), cilazapril (Hoffman-LaRoche) disclosed in J. Cardiovasc.Pharmacol. 9:39 (1987); R 31-2201 (Hoffman-LaRoche) disclosed in FEBSLett. 165:201 (1984); lisinopril (Merck), indalapril (delapril)disclosed in U.S. Pat. No. 4,385,051; indolapril (Schering) disclosed inJ. Cardiovasc. Pharmacol. 5:643, 655 (1983), spirapril (Schering)disclosed in Acta. Pharmacol. Toxicol. 59 (Supp. 5):173 (1986);perindopril (Servier) disclosed in Eur. J. clin. Pharmacol. 31:519(1987); quinapril (Warner-Lambert) disclosed in U.S. Pat. No. 4,344,949and CI925 (Warner-Lambert)([3S-[2-[R(*)R(*)]]3R(*)]-2-[2-[[1-(ethoxy-carbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylicacid HCl) disclosed in Pharmacologist 26:243, 266 (1984), WY-44221(Wyeth) disclosed in J. Med. Chem. 26:394 (1983).

Preferred ACE inhibitors are captopril, fosinopril, enalapril,lisinopril, quinapril, benazepril, fentiapril, ramipril and moexipril.

NEP/ACE inhibitors may also be employed herein in that they possessneutral endopeptidase (NEP) inhibitory activity and angiotensinconverting enzyme (ACE) inhibitory activity. Examples of NEP/ACEinhibitors suitable for use herein include those disclosed in U.S. Pat.Nos. 5,362,727, 5,366,973, 5,225,401, 4,722,810, 5,223,516, 4,749,688,U.S. Pat. No. 5,552,397, U.S. Pat. No. 5,504,080, U.S. Pat. No.5,612,359,U.S. Pat. No. 5,525,723, European Patent Application 0599,444,0481,522, 0599,444, 0595,610, European Patent Application 0534363A2,534,396 and 534,492, and European Patent Application 0629627A2.

Preferred are those NEP/ACE inhibitors and dosages thereof which aredesignated as preferred in the above patents/applications which U.S.patents are incorporated herein by reference; most preferred areomapatrilat, BMS 189,921([S—(R*,R*)]-hexahydro-6-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-2,2-dimethyl-7-oxo-1H-azepine-1-aceticacid (gemopatrilat)) and CGS 30440.

The angiotensin II receptor antagonist (also referred to herein asangiotensin II antagonist or AII antagonist) suitable for use hereinincludes, but is not limited to, irbesartan, losartan, valsartan,candesartan, telmisartan, tasosartan or eprosartan, with irbesartan,losartan or valsartan being preferred.

A preferred oral dosage form, such as tablets or capsules, will containthe ACE inhibitor or AII antagonist in an amount within the range fromabut 0.1 to about 500 mg, preferably from about 5 to about 200 mg andmore preferably from about 10 to about 150 mg.

For parenteral administration, the ACE inhibitor, angiotensin IIantagonist or NEP/ACE inhibitor will be employed in an amount within therange from about 0.005 mg/kg to about 10 mg/kg and preferably from about0.01 mg/kg to about 1 mg/kg.

Where a drug is to be administered intravenously, it will be formulatedin conventional vehicles, such as distilled water, saline, Ringer'ssolution or other conventional carriers.

It will be appreciated that preferred dosages of ACE inhibitor and AIIantagonist as well as other antihypertensives disclosed herein will beas set out in the latest edition of the Physician's Desk Reference(PDR).

Other examples of preferred antihypertensive agents suitable for useherein include omapatrilat (Vanlev®) amlodipine besylate (Norvasc®),prazosin HCl (Minipress®), verapamil, nifedipine, nadolol, diltiazem,felodipine, nisoldipine, isradipine, nicardipine, atenolol, carvedilol,sotalol, terazosin, doxazosin, propranolol, and clonidine HCl(Catapres®).

Diuretics which may be employed in combination with compounds of formulaI include hydrochlorothiazide, torasemide, furosemide, spironolactono,and indapamide.

Antiplatelet agents which may be employed in combination with compoundsof formula I of the invention include aspirin, clopidogrel, ticlopidine,dipyridamole, abciximab, tirofiban, eptifibatide, anagrelide, andifetroban, with clopidogrel and aspirin being preferred.

The antiplatelet drugs may be employed in amounts as indicated in thePDR. Ifetroban may be employed in amounts as set out in U.S. Pat. No.5,100,889.

Antiosteoporosis agents suitable for use herein in combination with thecompounds of formula I of the invention include parathyroid hormone orbisphosphonates, such as MK-217 (alendronate) (Fosamax®). Dosagesemployed will be as set out in the PDR.

In carrying our the method of the invention, a pharmaceuticalcomposition will be employed containing the compounds of structure I,with or without another therapeutic agent, in association with apharmaceutical vehicle or diluent. The pharmaceutical composition can beformulated employing conventional solid or liquid vehicles or diluentsand pharmaceutical additives of a type appropriate to the mode ofdesired administration. The compounds can be administered to mammalianspecies including humans, monkeys, dogs, etc. by an oral route, forexample, in the form of tablets, capsules, granules or powders, or theycan be administered by a parenteral route in the form of injectablepreparations. The dose for adults is preferably between 50 and 2,000 mgper day, which can be administered in a single dose or in the form ofindividual doses from 1-4 times per day.

A typical capsule for oral administration contains compounds ofstructure I (250 mg), lactose (75 mg) and magnesium stearate (15 mg).The mixture is passed through a 60 mesh sieve and packed into a No. 1gelatin capsule.

A typical injectable preparation is produced by aseptically placing 250mg of compounds of structure I into a vial, aseptically freeze-dryingand sealing. For use, the contents of the vial are mixed with 2 mL ofphysiological saline, to produce an injectable preparation.

The following abbreviations are employed in the Examples:

Ph=phenyl

Bn=benzyl

t-Bu=tertiary butyl

Me=methyl

Et=ethyl

TMS=trimethylsilyl

TMSN₃=trimethylsilyl azide

TMSCHN₂=trimethylsilyl diazomethane

TBS=tert-butyldimethylsilyl

TBDPS=tert-butyldiphenylsilyl

FMOC=fluorenylmethoxycarbonyl

Boc=tert-butoxycarbonyl

Cbz=carbobenzyloxy or carbobenzoxy or benzyloxycarbonyl

THF=tetrahydrofuran

Et₂O=diethyl ether

hex=hexanes

EtOAc=ethyl acetate

DMF=dimethyl formamide

MeOH=methanol

EtOH=ethanol

i-PrOH=IPA=isopropanol

DMSO=dimethyl sulfoxide

DME=1,2 dimethoxyethane

DCE=1,2 dichloroethane

HMPA=hexamethyl phosphoric triamide

HOAc or AcOH=acetic acid

TFA=trifluoroacetic acid

PTSA=pTSOH=para-toluenesulfonic acid

i-Pr₂NEt=diisopropylethylamine

Et₃N=TEA=triethylamine

Et₂NH=diethylamine

NMM=N-methyl morpholine

DMAP=4-dimethylaminopyridine

NaBH₄=sodium borohydride

NaBH(OAc)₃=sodium triacetoxyborohydride

DIBALH=diisobutyl aluminum hydride

LiAlH₄=lithium aluminum hydride

n-BuLi=n-butyllithium

Pd/C=palladium on carbon

PtO₂=platinum oxide

KOH=potassium hydroxide

NaOH=sodium hydroxide

LiOH=lithium hydroxide

K₂CO₃=potassium carbonate

NaHCO₃=sodium bicarbonate

H₂SO₄=sulfuric acid

KHSO₄=potassium hydrogen phosphate

DBU=1,8-diazabicyclo[5.4.0]undec-7-ene

EDC (or EDC.HCl) or EDCI (or EDCI.HCl) orEDAC=3-ethyl-3′-(dimethylamino)propyl-carbodiimide hydrochloride (or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride)

HOBT or HOBT.H₂O=1-hydroxybenzotriazole hydrate

HOAT=1-Hydroxy-7-azabenzotriazole

BOP reagent=benzotriazol-1-yloxy-tris(dimethylamino) phosphoniumhexafluorophosphate

NaN(TMS)₂=sodium hexamethyldisilazide or sodium

bis(trimethylsilyl)amide

Ph₃P=triphenylphosphine

Pd(OAc)₂=Palladium acetate

(Ph₃P)₄Pd^(o)=tetrakis triphenylphosphine palladium

DEAD=diethyl azodicarboxylate

DIAD=diisopropyl azodicarboxylate

Cbz-Cl=benzyl chloroformate

CAN=ceric ammonium nitrate

SiO₂=silica gel

SAX=Strong Anion Exchanger

SCX=Strong Cation Exchanger

Ar=argon

N₂=nitrogen

min=minute(s)

h or hr=hour(s)

L=liter

mL=milliliter

μL=microliter

μM=micromolar

g=gram(s)

mg=milligram(s)

mol=moles

mmol=millimole(s)

meq=milliequivalent

RT=room temperature

sat or sat'd=saturated

aq.=aqueous

TLC=thin layer chromatography

HPLC=high performance liquid chromatography

LC/MS=high performance liquid chromatography/mass spectrometry

MS or Mass Spec=mass spectrometry

NMR=nuclear magnetic resonance

NMR spectral data: s=singlet; d=doublet; m=multiplet; br=broad;t=triplet

mp=melting point

ee=enantiomeric excess

The following Examples represent preferred embodiments of the invention.

EXAMPLE 1

A solution of benzylamine (8.9 mL; 82 mmol) andchloromethyltrimethylsilane (5.0 g; 41 mmol) in MeCN (100 mL) was heatedat reflux for 16 h. The reaction was cooled to RT, filtered, and thefiltrate was concentrated in vacuo to a volume of ˜30 mL. H₂O (100 mL)was added and the mixture was extracted with hexane (2×20 mL). Thecombined organic extracts were washed with H₂O (3×20 mL), dried (MgSO₄)and concentrated in vacuo to give Part A compound (7.70 g; 49%) as anoil.

To a 0° C. solution of formaldehyde (4.6 g of a 37% aqueous solution;55.7 mmol) and 1N aqueous NaOH (5 drops) was added dropwise Part Acompound (7.70 g; 39.8 mmol). After the mixture had been stirred at 0°C. for 10 min, MeOH (4 mL) was added, followed by K₂CO₃ (4.0 g). Themixture was allowed to warm to RT and stirred at RT for 1 h. The organicphase was separated, more K₂CO₃ (2.0 g) was added, and the reaction wasstirred at RT for 12 h. Et₂O (20 mL) was then added to the mixture,which was filtered and the filtrate was concentrated in vacuo. Theresidual oil was distilled at reduced pressure (0.5 mm Hg; 80° C.) togive Part B compound (4.67 g; 49%) as an oil.

A mixture of 3-hydroxy phenylethanol (4.0 mg; 28 mmol), the mesylateExample 23 Part A compound (8.0 g; 28 mmol)

and K₂CO₃ (15.0 g; 110 mmol) in MeCN (150 mL) was stirred at 90° C. for5 h. At this point LC/MS showed that the reaction was complete. Thereaction was cooled to RT, solids were filtered off, and the filtratewas diluted with EtOAc (100 mL). The solution was successively washedwith aqueous 1 M HCl (10 mL), 1 M NaOH (10 mL) and H₂O (50 mL), dried(Na₂SO₄) and concentrated in vacuo. The residue was chromatographed(SiO₂; 2:1 hex:EtOAc) to give Part C compound (8.7 g; 96%) as an oil.

To a solution of Part C compound (4.0 g; 12.3 mmol) in CH₂Cl₂ (50 mL)were added Florisil™ (8.0 g), pyridinium chlorochromate (4.0 g; 19 mmol)and the reaction was stirred at RT for 3 h. The mixture was then dilutedwith anhydrous Et₂O (200 mL) and filtered. The chromium solid wasteswere washed with additional Et₂O (3×100 mL); the combined organicfiltrates were concentrated in vacuo to give the very crude and impurealdehyde (3.5 g) as an oil. A mixture of the aldehyde (3.5 g), PPTS (500mg; 0.50 mmol) and ethylene glycol (5.0 mL; 89 mmol) in toluene (50 mL)was heated to reflux in a Dean-Stark apparatus overnight. The reactionwas cooled to RT, washed with aqueous Na₂CO₃ and brine (50 mL each),dried (Na₂SO₄), and concentrated in vacuo to give an oil. This materialwas chromatographed (SiO₂; 3:1 hexane:EtOAc) to give Part D compound(1.35 g; 30%) as a clear oil.

A solution of Part D compound (1.35 g; 3.7 mmol), glacial acetic acid(10 mL) and H₂O (2 mL) was heated at 80° C. for 48 h. H₂O (100 mL) wasadded and the mixture was extracted with EtOAc (2×20 mL). The combinedorganic extracts were washed with H₂O (2×100 mL), saturated aqueousNaHCO₃ (2×100 mL), dried (Na₂SO₄), and concentrated in vacuo to givePart E compound (1.24 g; 99%) as a brown oil.

A mixture of Part E compound (500 mg; 1.55 mmol) andtert-butyl(triphenylphosphoranylidene)acetate (600 mg; 1.59 mmol) intoluene (100 mL) was heated to reflux for 1 h. Analytical HPLC showedthat the reaction was complete. After cooling, volatiles were removed invacuo and the residue was chromatographed (SiO₂; hex:EtOAc 3:1) to givePart F compound (390 mg; 60%) as an oil.

A mixture of Part E compound (100 mg; 0.238 mmol), Part B compound (85mg; 0.36 mmol) and a catalytic amount of TFA (1 μL) in toluene (1.0 mL)was stirred at RT for 3 h. TLC showed that the reaction was complete atthis point. Volatiles were removed in vacuo and the residue waschromatographed (SiO₂; hex:EtOAc 1:1) to provide Part G compound (110mg; 93%) as an oil.

A solution of Part G compound (22 mg; 0.036 mmol) and TFA (1 mL) inCH₂Cl₂ (2 mL) was stirred at RT for 6 h. Volatiles were removed in vacuoand the residue was purified by preparative HPLC (YMC reverse-phase ODS20×100 mm column; flow rate=20 mL/min; 10 min continuous gradient from30:70 B:A to 100% B+5 min hold-time at 100% B, where solventA=90:10:0.1H₂O:MeOH:TFA and solvent B=90:10:0.1 MeOH:H₂O:TFA) to givethe racemic title compound (17 mg; 97%). [M+H]⁺=497.2

EXAMPLE 2

A mixture of Example 1 Part G compound (94 mg; 0.19 mmol) and 10% Pd/C(10 mg) in MeOH (10 mL) under an atmosphere of H₂ was stirred at RT for3 h. At this point analytical HPLC showed that the reaction wascomplete. The catalyst was filtered off on a pad of Celite® and thefiltrate was concentrated in vacuo to give crude Part A compound whichwas used in the next reaction without further purification.

To a 0° C. solution of crude Part A compound (10 mg; 0.022 mmol) andDMAP (150 mg; 1.23 mmol) in pyridine (1 mL) was added dropwise ethylchloroformate (500 μL; 5.23 mmol). The reaction mixture was stirred at60° C. for 2 h. At this point TLC indicated that all starting materialhad been consumed. Volatiles were removed in vacuo; the residue wasdissolved in CH₂Cl₂ (1 mL) and TFA (1.5 mL) and the reaction was stirredat RT for 1 h. Volatiles were removed in vacuo and the residue waspartitioned between EtOAc (5 mL) and H₂O (3 mL). The organic phase waswashed with H₂O (2×3 mL) and concentrated in vacuo. The residue waspurified by preparative HPLC (as described for Example 1) to furnish thetitle compound (5.6 mg; 53%).

[M+H]⁺=479.3

EXAMPLE 3

Example 3 (6.6 mg; 57%) was synthesized employing the proceduredescribed in Example 2, except that phenyl chloroformate was used in thesequence instead of ethyl chloroformate.

[M+H]⁺=527.2

EXAMPLE 4

A mixture of Example 2 Part A compound (20 mg; 0.043 mmol), bromobenzene(10 mg; 0.263 mmol), 1,3-bis (diphenylphosphino)propane (DPPP; 2 mg;4.8×10⁻³ mmol), sodium tert-butoxide (2 mg; 0.018 mmol) andPd₂(dibenzylacetone)₃ (1 mg; 1×10⁻³ mmol) in toluene (2 mL) was stirredat 90° C. for 6 h. At this point HPLC showed that all starting materialhad been consumed. The reaction mixture was cooled to RT and partitionedbetween EtOAc (10 mL) and aqueous 1 N HCl (10 mL). The organic phase waswashed with H₂O (2×20 mL), dried (Na₂SO₄), and concentrated in vacuo.The residue was dissolved in TFA:CH₂Cl₂ (1 mL of a 1:1 solution) and thereaction was stirred at RT for 1 h. Volatiles were removed in vacuo andthe residue was purified by preparative HPLC (as described forExample 1) to provide the title compound (7 mg; 48%) as an oil.

[M+H]⁺=483.2

EXAMPLE 5

To a −78° C. solution of (CF₃CH₂O)₂P(O)CH₂CO₂CH₃ (1.47 g; 4.62 mmol) and18-crown-6 (6.10 g; 23 mmol) in anhydrous THF (50 mL) under N₂ was addeddropwise potassium hexamethyldisilazide (9.2 mL of a 0.5M solution intoluene; 4.62 mmol). The solution was stirred at −78° C. for 30 min,after which a solution of the aldehyde (Example 1 Part E compound; 1.24g; 3.86 mmol) in THF (50 mL) was added dropwise. The reaction mixturewas stirred for 30 min at −78° C., after which excess saturated aqueousNH₄Cl (50 mL) was added. The mixture was allowed to warm to RT andextracted with Et₂O (3×30 mL). The combined organic extracts were dried(Na₂SO₄), concentrated in vacuo, and the residue was chromatographed(SiO₂; 3:1 hexane:EtOAc) to give Part A compound (343 mg; 23%) as anoil.

A mixture of Part A compound (343 mg; 0.908 mmol), Example 1 Part Bcompound (300 mg; 1.26 mmol) and a catalytic amount of TFA (5 μL) intoluene (5.0 mL) was stirred at RT for 3 h. TLC showed that the reactionwas complete at this point. Volatiles were removed in vacuo and theresidue was chromatographed (SiO₂; hex:EtOAc 1:1) to provide Part Bcompound (450 mg; 98%) as an oil.

A solution of Part B compound (27 mg; 0.053 mmol), aqueous LiOH (1 mL ofa 1 M solution) and THF (2 mL) was stirred at RT for 5 h. At this point,LC/MS indicated that the reaction was complete. The mixture wasacidified with aqueous HCl (5 mL of a 1 M solution) and extracted withEtOAc (10 mL). The organic phase was washed with H₂O (2×5 mL), dried(Na₂SO₄) and concentrated in vacuo. The residue was purified bypreparative HPLC (as described for Example 1) to give the title compound(24 mg; 91%) as a white lyophilate.

[M+H]⁺=497.3

EXAMPLE 6

A mixture of Example 5 Part B compound (580 mg; 1.17 mmol) and 10% Pd/C(50 mg) in MeOH (25 mL) under an atmosphere of H₂ was stirred at RT for18 h. At this point analytical HPLC showed that the reaction wascomplete. The catalyst was filtered off (using a pad of Celite®) and thefiltrate was concentrated in vacuo to give crude Part A compound (400mg; 81%) as an oil which was used in the next reaction without furtherpurification.

To a 0° C. solution of crude Part A compound (10 mg; 0.022 mmol) andDMAP (150 mg; 1.23 mmol) in CH₂Cl₂ (1 mL) was added dropwise ethylchloroformate (500 μL; 5.23 mmol). The reaction mixture was then stirredat RT for 5 h. At this point TLC indicated that all starting materialhad been consumed. Volatiles were removed in vacuo and the residue wasdissolved in a solution of THF (1 mL) and aqueous LiOH (1 mL of a 1 Msolution) and the reaction was stirred at RT for 12 h. The reactionmixture was acidified with aqueous HCl (2 mL of a 1 M solution) andextracted with EtOAc (10 mL). The organic phase was washed with H₂O (2×5mL), dried (Na₂SO₄) and concentrated in vacuo. The residue was purifiedby preparative HPLC (as described for Example 1) to give the titlecompound (6.0 mg; 56%) as a white lyophilate.

[M+H]⁺=479.3

EXAMPLE 7

Example 7 compound (6.2 mg; 53%) was synthesized employing the proceduredescribed in Example 6, except that phenyl chloroformate was used in thesequence instead of ethyl chloroformate.

[M+H]⁺=479.3

EXAMPLE 8

A mixture of Example 6 Part A compound (30 mg; 0.071 mmol),phenylboronic acid (15 mg; 0.123 mmol), Cu(OAc)₂ (4 mg; 0.022 mmol),myristic acid (3 mg; 0.013 mmol) and 2,6 lutidine (10 μL; 0.056 mmol) intoluene (2 mL) was stirred at RT for 24 h in air. At this point HPLCshowed that product had been formed. The reaction mixture was elutedthrough an SiO₂ cartridge with 1:1 hexane:EtOAc. The combined eluentfractions were concentrated in vacuo and the residue was taken up inaqueous LiOH (0.5 mL of a 1 M solution) and THF (1 mL). The reaction wasstirred at RT for 2 h; TLC indicated that the reaction was complete atthis point. Volatiles were removed in vacuo and the residue was purifiedby preparative HPLC (as described for Example 1) to provide the titlecompound (6 mg; 17%) as an oil.

[M+H]⁺=483.2

EXAMPLE 9

To a −78° C. solution of (CF₃CH₂O)₂P(O)CH₂CO₂CH₃ (372 mg; 1.17 mmol) and18-crown-6 (1.55 g; 5.85 mmol) in anhydrous THF (5 mL) under N₂ wasadded dropwise potassium hexamethyldisilazide (2.34 mL of a 0.5 Msolution in toluene; 1.17 mmol). The solution was stirred at −78° C. for30 min, after which a solution of the aldehyde Example 47 Part Bcompound (300 mg; 0.977 mmol)

in THF (5.5 mL) was added dropwise. The reaction mixture was stirred for30 min at −78° C., after which excess saturated aqueous NH₄Cl (50 mL)was added. The mixture was allowed to warm to RT and extracted with Et₂O(3×30 mL). The combined organic extracts were dried (Na₂SO₄),concentrated in vacuo, and the residue was chromatographed (SiO₂; 3:1hexane:EtOAc) to give Part A compound (317 mg; 89%) as an oil.

A mixture of Part A compound (317 mg; 0.87 mmol), Example 1 Part Bcompound (300 mg; 1.26 mmol) and a catalytic amount of TFA (5 μL) intoluene (5.0 mL) was stirred at RT for 3 h. TLC showed that the reactionwas complete at this point. Volatiles were removed in vacuo and theresidue was chromatographed (SiO₂; hex:EtOAc 1:1) to provide Part Bcompound (400 mg; 92%) as an oil.

A solution of Part B compound (13 mg; 0.026 mmol) in aqueous LiOH (0.5mL of a 1 M solution) and THF (1 mL) was stirred at RT for 2 h; TLCindicated that the reaction was complete at this point. The reactionmixture was acidified with aqueous HCl (2 mL of a 1 M solution) andextracted with EtOAc (10 mL). The organic phase was washed with H₂O (2×5mL), dried (Na₂SO₄) and concentrated in vacuo. The residue was purifiedby preparative HPLC (as described for Example 1) to provide the titlecompound (6 mg; 48%) as an oil.

[M+H]⁺=483.2

EXAMPLE 10

A mixture of Example 9 Part B compound (400 mg; 0.805 mmol) and 10% Pd/C(50 mg) in MeOH (15 mL) under an atmosphere of H₂ was stirred at RT for5 h. At this point analytical HPLC showed that the reaction wascomplete. The catalyst was filtered off (using a pad of Celite®) and thefiltrate was concentrated in vacuo to give crude Part A compound (280mg; 85%) as an oil which was used in the next reaction without furtherpurification.

To a 0° C. solution of crude Part A compound (15 mg; 0.037 mmol) andDMAP (13 mg; 0.1 mmol) in CH₂Cl₂ (1 mL) was added dropwise ethylchloroformate (7 μL; 0.06 mmol). The reaction mixture was then stirredat RT for 3 h. At this point HPLC indicated that all starting materialhad been consumed. TFA in CH₂Cl₂ was added (1 mL of a 1:1 solution) andthe reaction was stirred at RT for 1 h. Volatiles were removed in vacuoand the residue was purified by preparative HPLC (as described forExample 1) to give the title compound (6.4 mg; 36%) as an oil.

[M+H]⁺=465.3

EXAMPLE 11

The racemic title compound (2.7 mg; 14%) was prepared employing theprocedure described in Example 10, except that phenyl chloroformate (8μL; 0.06 mmol) was used in the sequence instead of ethyl chloroformate.

[M+H]⁺=513.4

EXAMPLE 13

A mixture of Ph₃P═CHCO₂tBu (200 mg; 0.53 mmol) and the aldehyde Example47 Part B compound (150 mg; 0.49 mmol)

in toluene (20 mL) was heated at 100° C. for 2 h. At this point LC/MSindicated that all starting aldehyde had been consumed. The reactionmixture was cooled to RT and volatiles were removed in vacuo. Theresidue was chromatographed (SiO₂; 3:1 hexane:EtOAc) to provide Part Acompound (120 mg; 60%) as a clear oil.

A mixture of Part A compound (120 mg; 0.30 mmol), Example 1 Part Bcompound (100 mg; 0.421 mmol) and a catalytic amount of TFA (5 μL) inCH₂Cl₂ (5.0 mL) was stirred at RT for 24 h. HPLC showed that thereaction was complete at this point. Volatiles were removed in vacuo andthe residue was chromatographed (SiO₂; hex:EtOAc 3:1) to provide Part Bcompound (143 mg; 88%) as an oil.

A solution of Part B compound (20 mg; 0.037 mmol) in aqueous LiOH (0.5mL of a 1 M solution) and THF (1 mL) was stirred at RT for 2 h; TLCindicated that the reaction was complete at this point. The reactionmixture was acidified with aqueous HCl (2 mL of a 1 M solution) andextracted with EtOAc (10 mL). The organic phase was washed with H₂O (2×5mL), dried (Na₂SO₄) and concentrated in vacuo. The residue was purifiedby preparative HPLC (as described for Example 1) to provide the titlecompound (6 mg; 33%) as an oil.

[M+H]⁺=483.2

EXAMPLE 14

A mixture of Example 10 Part B compound (143 mg; 0.265 mmol) and 10%Pd/C (30 mg) in MeOH (10 mL) under an atmosphere of H₂ was stirred at RTfor 3 h. At this point analytical HPLC showed that the reaction wascomplete. The catalyst was filtered off (using a pad of Celite®) and thefiltrate was concentrated in vacuo to give crude Part A compound (82 mg;69%) as an oil which was used in the next reaction without furtherpurification.

To a 0° C. solution of crude Part A compound (15 mg; 0.033 mmol) andDMAP (15 mg; 0.122 mmol) in CH₂Cl₂ (1 mL) was added dropwise ethylchloroformate (7 μL; 0.06 mmol). The reaction mixture was then stirredat RT for 3 h. At this point HPLC indicated that all starting materialhad been consumed. TFA in CH₂Cl₂ was added (1 mL of a 1:1 solution) andthe reaction was stirred at RT for 1 h. Volatiles were removed in vacuoand the residue was purified by preparative HPLC (as described forExample 1) to give the title compound (16 mg; 57%) as an oil.

[M+H]⁺=465.3

EXAMPLE 15

Example 15 compound (19 mg; 62%) was prepared employing the procedure asdescribed in Example 11, except that phenyl chloroformate (8 μL; 0.04mmol) was used in the sequence instead of ethyl chloroformate.

[M+H]⁺=513.4

EXAMPLE 16

The procedure of Example 8 was essentially followed to prepare the titlecompound.

A mixture of Example 14 Part A compound (40 mg; 0.089 mmol),phenylboronic acid (12 mg; 0.10 mmol), Cu(OAc)₂ (1 mg; 5.5×10⁻³ mmol),myristic acid (1 mg; 4.3×10⁻³ mmol) and 2,6 lutidine (18 μL; 0.16 mmol)in toluene (1 mL) was stirred at RT for 24 h in air. At this point HPLCshowed that product had been formed. The reaction mixture was filtered,and the filtrate was concentrated in vacuo. The residue was dissolved ina solution of TFA/CH₂Cl₂ (1 mL of a 1:1 mixture). The reaction wasstirred at RT for 1 h; TLC indicated that the reaction was complete atthis point. Volatiles were removed in vacuo and the residue was purifiedby preparative HPLC (as described for Example 1) to provide the titlecompound (4 mg; 9%) as an oil.

[M+H]⁺=469.2

EXAMPLE 17

To a −74° C. solution of tert-butyl propiolate (0.808 g; 6.4 mmol) inanhydrous THF (10 mL) was added n-BuLi (2.60 mL of a 2.5 M solution inhexane) dropwise. The reaction mixture was stirred at −74° C. for 30min, after which a solution of the aldehyde Example 436 Part A compound(1.79 g; 5.83 mmol)

in anhydrous THF (10 mL) was added dropwise at −74° C. (temperaturereached −68° C. during addition). The reaction mixture was stirred at−70° C. for 1 h, after which it was quenched by dropwise addition ofsaturated aqueous NH₄Cl (10 mL). The mixture was allowed to warm to RT,then extracted with EtOAc (2×20 mL). The combined organic extracts werewashed with water, dried (Na₂SO₄) and concentrated in vacuo to providecrude Part A compound, which was used in the next step without furtherpurification.

To a solution of Part A compound (1.75 g; 4.08 mmol) in CH₂Cl₂ (10 mL)were successively added acetic anhydride (0.75 g; 8.2 mmol), pyridine(1.16 g; 16.3 mmol) and DMAP (10 mg). The reaction was stirred at RT for2 h, after which LC/MS indicated that the reaction was complete. EtOAc(150 mL) was added and the solution was washed with aqueous 1 M HCl (2×)and H₂O, then concentrated in vacuo. The residual oil waschromatographed (SiO₂; 3:1 hexane:EtOAc) to provide Part B compound(1.79 g; 92%) as an oil.

A solution of 4-methoxybenzylamine (11.2 g; 82 mmol) and Me₃SiCH₂Cl (5.0g; 41 mmol) in MeCN (50 mL) was refluxed under an atmosphere of N₂ for16 h. The reaction mixture was then cooled to RT and filtered. Thefiltrate was concentrated in vacuo to ˜30 mL in volume. H₂O (100 mL) wasadded and the mixture was extracted with hexane (2×20 mL). The combinedorganic extracts were washed with H₂O (3×20 mL), dried (MgSO₄) andconcentrated in vacuo to provide crude Part C compound (7.6 g; 41%) asan oil, which was used in the next step without further purification.

To a 0° C. solution of 37% aqueous formaldehyde (2.8 g; 34 mmol) wasadded dropwise crude Part C compound (7.6 g; 34 mmol) followed by 5drops of aqueous 1 N NaOH (in order to neutralize the formic acid in theformaldehyde). The reaction mixture was stirred at 0° C. for 10 min,after which MeOH (5 mL) was added in one portion. K₂CO₃ (4 g) was addedto absorb the aqueous phase, after which the mixture was stirred at RTfor 1 h and then filtered. Additional K₂CO₃ (2 g) was added to thefiltrate and the mixture was stirred at RT for an additional 12 h. Et₂O(20 mL) was then added and the mixture was filtered; the filtrate wasconcentrated in vacuo and the residual oil was distilled under reducedpressure (bp=80° C.@0.5 mm Hg) to give Part D compound (4.2 g; 46%) as aclear oil.

A mixture of Part B compound (130 mg; 0.273 mmol), Part D compound (73mg; 0.273 mmol) and TFA (catalytic amount; several drops) in CH₂Cl₂ (2mL) was stirred at RT for 2 h. At this point the reaction was completeby TLC. Volatiles were removed in vacuo and the mixture waschromatographed (SiO₂; 3:1 hexane:EtOAc) to provide Part E compound (171mg; 98%) as an oil.

A solution of Part E compound (360 mg; 0.564 mmol), (Ph₃P)₂PdCl₂ (4 mg;0.006 mmol) and formic acid/Et₃N (0.50 mL of a 1:1 4M solution indioxane; 1.69 mmol) in dioxane (5 mL) was refluxed N₂ for 30 min. Atthis point LC-MS indicated that all starting material had been consumed.The reaction mixture was cooled to RT, diluted with EtOAc (5 mL) andwashed with H₂O (2×10 mL). The organic phase was dried (Na₂SO₄) andconcentrated in vacuo. The residue was chromatographed (ISCOchromatography apparatus; 25 g SiO₂ column; continuous gradient fromhexane->70:30 hexane:EtOAc) to provide Part F compound (114 mg; 35%) inaddition to the pyrrole (Part G compound; 80 mg; 25%)

as well as the pyrrolidine (Part H compound; 25 mg; 8%)

as byproducts.

To a −78° C. solution of Part F compound (114 mg; 0.1969 mmol) in CH₂Cl₂(1 mL) was added CH₃CHClOCOCl (45 μL; 0.40 mmol) The reaction mixturewas stirred at −78° C. for 30 min, then was allowed to warm to RT andstirred at RT for 1 h. At this point, HPLC indicated that all startingmaterial had been consumed. Volatiles were removed in vacuo and MeOH (5mL) was added; the solution was then stirred at RT for 8 h. Volatileswere removed in vacuo and the residue was purified by preparative HPLC(YMC reverse-phase ODS 30×250 mm column; flow rate=25 mL/min; 30 mincontinuous gradient from 30:70 B:A to 100% B+10 min hold-time at 100% B,where solvent A=90:10:0.1H₂O:MeOH:TFA and solvent B=90:10:0.1MeOH:H₂O:TFA) to provide Part I compound (81 mg; 89%) as a TFA salt.

A solution of Part I compound (18 mg; 0.032 mmol), phenyl chloroformate(6.3 μL; 0.05 mmol) and DMAP (11 mg; 0.09 mmol) in CH₂Cl₂ (3 mL) wasstirred at RT for 30 min. EtOAc (10 mL) was then added and the mixturewas successively washed with H₂O (2×20 mL) and aqueous 1 N HCl (10 mL),then dried (Na₂SO₄). Volatiles were removed in vacuo and the residualoil was dissolved in TFA/CH₂Cl₂ (1 mL of a 1:1 mixture) and the reactionwas stirred at RT for 1 h, after which volatiles were removed in vacuo.The residue was purified by preparative HPLC (as described forExample 1) to provide the title compound (13 mg; 78%) as an oil.

[M+H]⁺=525.1

EXAMPLE 18

A solution of Example 17 Part J compound (25 mg; 0.054 mmol), ethylchloroformate (11 mg; 0.10 mmol) and DMAP (61 mg; 0.50 mmol) in CH₂Cl₂(2 mL) was stirred at RT for 30 min. EtOAc (10 mL) was then added andthe mixture was successively washed with H₂O (2×20 mL) and aqueous 1 NHCl (10 mL), then dried (Na₂SO₄). Volatiles were removed in vacuo andthe residual oil was dissolved in TFA/CH₂Cl₂ (1 mL of a 1:1 mixture) andthe reaction was stirred at RT for 1 h, after which volatiles wereremoved in vacuo. The residue was purified by preparative HPLC (usingthe same conditions as described for Example 1) to provide Example 16compound (17 mg; 66%) as an oil.

[M+H]⁺=477.1

EXAMPLE 19

Example 19 compound was prepared from Example 17 Part G compound (16 mg;0.035 mmol) with phenyl chloroformate (13 μL; 0.10 mmol) using the2-step sequence as employed in the synthesis of Example 17 from Example17 Part J compound. Example 19 compound was obtained (9 mg; 49%) as awhite solid after preparative HPLC (using the same conditions asdescribed in Example 1).

[M+H]⁺=525.1

EXAMPLE 19A

To a RT solution of D-(1S)-(−)-2,10-camphorsultam (1.0 g; 4.64 mmol) inanhydrous toluene (5 mL) under an atmosphere of argon was added Me₃Al(2.3 mL of a 2.0 M solution in toluene; 4.6 mmol). The solution wasstirred at RT for 1 h, after which (CF₃CH₂O)₂P(O)CH₂CO₂CH₃ (1.50 g; 4.71mmol) was added. The reaction was stirred at 75° C. for 3 days, cooledto RT, and partitioned between saturated aqueous NH₄Cl (50 mL) and Et₂O(25 mL). The organic phase was dried (MgSO₄) and concentrated in vacuo.The residue was chromatographed (SiO₂; hexane:EtOAc 3:1) and furtherpurified by preparative HPLC (YMC ODS reverse phase 30×250 mm column;flow rate=25 mL/min; 30 min continuous gradient from 80:20 A:B to 100%B; where A=90:10:0.1H₂O:MeOH:TFA; B=90:10:0.1 MeOH:H₂O:TFA, then 15 minhold at 100% B) to give Part A compound (491 mg; 21%) as an oil.

To a −78° C. solution of Part A compound (491 mg; 0.98 mmol) and18-crown-6 (2.1 g; 8 mmol) in THF (20 mL) under an atmosphere of N₂ wasadded dropwise a solution of KN(TMS)₂ (2.35 mL of a 0.5 M solution intoluene; 1.18 mmol). The reaction was stirred at −78° C. for 30 min,after which a solution of the aldehyde (Example 1 Part E compound; 377mg; 1.18 mmol) in THF (5 mL) was added and the reaction was stirred at−78° C. for a further 30 min. Saturated aqueous NH₄Cl (5 mL) was thenadded slowly and the reaction was allowed to warm to RT. The mixture wasextracted with Et₂O (3×30 mL), dried (Na₂SO₄) and concentrated in vacuo.The crude product was chromatographed (SiO₂; hexane:EtOAc 3:1) toprovide Part B compound (Z-isomer; 100 mg; 18%) as an oil. In additionthe isomeric Part C compound

(E-isomer; 50 mg; 9%) was also obtained.

A mixture of Part B compound (100 mg; 0.178 mmol), Example 1 Part Bcompound (100 mg; 0.421 mmol) and a catalytic amount of TFA (5 μL) intoluene (2.0 mL) was stirred at RT for 3 h. TLC showed that the reactionwas complete. The reaction mixture was partitioned between EtOAc (10 mL)and saturated aqueous NaHCO₃ (20 mL). The organic phase was dried(Na₂SO₄) and concentrated in vacuo. The residue was chromatographed(SiO₂; hex:EtOAc 3:1) to provide Part C compound (56 mg; 45%) as an oil.

A mixture of Part C compound (56 mg; 0.081 mmol) and 10% Pd/C (30 mg) inMeOH (5 mL+1 drop of HOAc) was stirred under an atmosphere of H₂ at RTfor 5 h. The mixture was filtered, and the filtrate was concentrated invacuo to give Part D compound (42 mg; 85%) as an oil.

A mixture of Part D compound (20 mg; 0.033 mmol), DMAP (12 mg; 0.1 mmol)and ethyl chloroformate (5 mg; 0.05 mmol) in CH₂Cl₂ (1 mL) was stirredat RT for 30 min, then was partitioned between EtOAc (10 mL) and H₂O (20mL). The organic phase was washed with H₂O and aqueous 1 M HCl (10 mLeach), dried (Na₂SO₄) and concentrated in vacuo. The residue waschromatographed (SiO₂; continuous gradient from 100% hexane to 30:70hexane:EtOAc over 25 min) to give Part E compound (4 mg; 18%) as an oil.

A solution of Part E compound (4 mg; 5.9×10⁻³ mmol) in aqueous LiOH (1mL of a 1 N solution) and THF (2 mL) was stirred at RT for 3 h, then waspartitioned between excess aqueous 1 M HCl and EtOAc. The organic phasewas washed with H₂O, dried (Na₂SO₄) and concentrated in vacuo. Theresidue was purified by preparative HPLC (as described for the synthesisof Example 1) to give the title compound (0.9 mg; 32%).

[M+H]+=479.2

Chiral analytical HPLC (Daicel Chiralcel OJ-H 4.6×250 mm column): flowrate=1 mL/min; isocratic conditions=80:20 A:B, where A=heptane+0.1% TFAand B=50:50:0.1 MeOH:EtOH:TFA; detector wavelength=220 nm; retentiontime=20.0 min; ee=95%

The rest of the material was the chiral epimerized trans isomer:

EXAMPLE 19B COMPOUND

EXAMPLE 20

Example 20 compound (0.5 mg; 16%) was prepared from Example 19A Part Dcompound (using the same sequence as the synthesis of Example 19A fromExample 19A Part D compound). [M+H]+=527.2

Chiral analytical HPLC (Daicel Chiralcel OD 4.6×250 mm column): flowrate=1 mL/min; isocratic conditions=85:15 A:B, where A=heptane+0.1% TFA;B=50:50:0.1 MeOH:EtOH:TFA; detector wavelength=220 nm; retentiontime=21.3 min; ee=93%

EXAMPLE 21

Part A compound (630 mg; 27%) was synthesized in exactly the same way asExample 19 Part A compound except that L-(1S)-(−)-2,10-camphorsultam(1.0 g) was used in place of D-(1R)-(+)-2,10-camphorsultam.

To a −78° C. solution of Part A compound (630 mg; 1.26 mmol) and18-crown-6 (2.66 g; 10.1 mmol) in anhydrous THF (25 mL) under N₂ wasadded dropwise a solution of KN(TMS)₂ (2.51 mL of a 0.5 M solution intoluene; 1.26 mmol). The reaction was stirred at −78° C. for 15 min,after which a solution of Example 1 Part E compound (610 mg; 1.90 mmol)in THF (5 mL) was added dropwise. The reaction was stirred at −78° C.for a further 30 min, then quenched by cautious addition of excess H₂O.The reaction was allowed to warm to RT and partitioned between saturatedaqueous NH₄Cl and EtOAc. The organic phase was washed with H₂O andbrine, dried (MgSO₄) and concentrated in vacuo. The residue waschromatographed (SiO₂; continuous gradient from 100% hexane to 100%EtOAc over 50 min) to provide the Z-olefin Part B compound (293 mg; 28%)as an oil. In addition, the corresponding E-olefin Part C compound (149mg; 14%) was also obtained.

To a solution of Part B compound (290 mg; 0.517 mmol) in toluene (1.3mL) were successively added Example 1 Part B compound (270 mg; 1.14mmol) and a catalytic amount of TFA (1 μL). The reaction was stirred atRT for 3 h, then was partitioned between EtOAc and saturated aqueousNaHCO₃. The organic phase was washed with brine, dried (MgSO₄) andconcentrated in vacuo. The residue was chromatographed (SiO₂; continuousgradient from 100% hexane to 100% EtOAc over 40 min) to provide Part Dcompound (176 mg; 49%) as well as a diastereomeric product (41 mg; 11%),which corresponds to Example 19 Part C compound.

A mixture of Part D compound (87 mg; 0.126 mmol) and 10% Pd/C (42 mg) inMeOH:EtOAc (2.5 mL of a 4:1 solution) was stirred under an atmosphere ofH₂ at RT for 24 h. The mixture was filtered and the filtrate wasconcentrated in vacuo to give Part E compound (70 mg; 92%) as an oil.

A mixture of Part E compound (35 mg; 0.058 mmol), Et₃N (16 μL; 0.12mmol), DMAP (one crystal) and phenyl chloroformate (15 μL; 0.12 mmol) inCH₂Cl₂ (1 mL) was stirred at RT for 2 h, then was partitioned betweenaqueous 1 N HCl and EtOAc. The organic phase was washed with H₂O andbrine, dried (MgSO₄) and concentrated in vacuo. The residue waschromatographed (SiO₂; continuous gradient from 100% hexane to 100%EtOAc over 35 min) to give Part F compound (30 mg; 72%) as an oil.

A mixture of Part F compound (15 mg; 0.021 mmol) and LiOH.H₂O (40 mg;0.95 mmol) in THF/H₂O (4 mL of a 2:1 solution) was stirred at RT for 18h. EtOAc was added and the reaction acidified to pH˜2 with aqueous 1 NHCl. The organic phase was washed with brine, dried (Na₂SO₄) andconcentrated in vacuo. The residue was chromatographed (SiO₂; stepwisegradient from 1:1 hex:EtOAc to 10:10:1 hex:EtOAc:acetic acid) to givethe title compound (6.5 mg; 60%) as a white solid.

[M+H]⁺=527.6

Chiral analytical HPLC (Daicel Chiralcel OD 4.6×250 mm column): flowrate=1 mL/min; isocratic conditions=85:15 A:B, where A=heptane+0.1% TFA;B=50:50:0.1 MeOH:EtOH:TFA; detector wavelength=220 nm; retentiontime=15.6 min; ee=99%

EXAMPLE 21 Alternative Synthesis

To a RT solution of ethyl trimethylsilylpropynoate (2.65 g; 15.6 mmol)and aldehyde Example 436 Part A compound (4.0 g; 13.0 mmol)

in CH₂Cl₂ (100 mL) were successively added potassium fluoride (910 mg;15.6 mmol) and 18-crown-6 (1.26 g; 4.7 mmol). The reaction mixture wasstirred at RT for 18 h, after which a solution of concentrated HCl (5mL) in MeOH (20 mL) was added slowly. The solution was stirred for 3 hat RT, then washed with aqueous 1 N HCl and brine. The organic phase wasdried (MgSO₄) and concentrated in vacuo. The residue was dissolved inCH₂Cl₂ (40 mL) and acetyl chloride (1.20 g; 15.6 mmol) and Et₃N (2.2 mL;15.6 mmol) were successively added slowly to this solution. The reactionwas stirred at RT for 30 min, then washed with brine and saturatedaqueous NaHCO₃. The organic phase was dried (MgSO₄) and concentrated invacuo. The crude product was chromatographed (SiO₂; heptane:EtOAc 7:3)to give Part A compound (3.26 g; 56%) as a pale yellow oil.

To a RT solution of Part A compound (2.50 g; 5.60 mmol) in CH₂Cl₂ (40mL) was added a solution of Example 1 Part B compound (1.70 g; 7.2 mmol)in CH₂Cl₂ (40 mL). The solution was stirred at RT for 10 min, afterwhich TFA (0.50 mL) was added dropwise. The reaction was stirred at RTfor 1 h, after which HPLC indicated that 30% of Part A compound stillremained. Additional Example 1 Part A compound (0.57 g; 2.4 mmol) wasadded and the reaction was stirred for 30 min longer. The solution waswashed with saturated aqueous NaHCO₃, dried (MgSO₄) and concentrated invacuo. The residue was chromatographed (SiO₂; heptane:EtOAc 6:4) to givecrude Part B compound (2.3 g) as a pale yellow oil.

A mixture of crude Part B compound (2.3 g), 10% Pd/C (600 mg) andconcentrated HCl (5 drops) in MeOH (40 mL) was stirred under anatmosphere of H₂ (60 psi) for 96 h. The catalyst was filtered off(Celite®) and the filtrate was concentrated in vacuo; the residue waspartitioned between EtOAc and aqueous 1 N NaOH. The organic phase wasdried (Na₂SO₄) and concentrated in vacuo. The residue waschromatographed (SiO₂; CH₂Cl₂:MeOH 10:1) to give racemic Part C compound(1.70 mg; 70% for 2 steps) as a pale yellow oil. The individualenantiomers were separated at this point by preparative HPLC under thefollowing conditions: Chiralcel OD chiral column, 5 cm×50 cm; 20 μM;Flow rate=45 mL/min; isocratic solvent system=80% heptane+0.1% Et₂NH &20% IPA+0.1% Et₂NH. Part C compound (1.72 g) was chromatographed in 3runs. The first fraction elutes under these conditions @ 45 min−1 hourand was subsequently determined to be the (3R,4S) enantiomer (see below)(Part D compound).

The second fraction elutes under these conditions @ 1 hour-1 hour 15min. This fraction was subsequently determined to be the (3S,4R)enantiomer (see below) (Part E compound).

EXAMPLE 22

The title compound (4.3 mg; 16% for 2 steps) was prepared from Example21 Part E compound using the same 2-step sequence as for the synthesisof Example 21.

[M+H]⁺=479.5

Chiral analytical HPLC (Daicel Chiralcel OD 4.6×250 mm column): flowrate=1 mL/min; isocratic conditions=80:20 A:B, where A=heptane+0.1% TFA;B=50:50:0.1 MeOH:EtOH:TFA; detector wavelength=220 nm; retentiontime=14.6 min; ee=99%

EXAMPLE 23

To a −5° C. solution of 5-phenyl-2-methyl-oxazole-4-ethanol (20.00 g,0.098 mol) in CH₂Cl₂ (100 mL) was added methanesulfonyl chloride (12.40g, 0.108 mol) in one portion (exothermic reaction). After recooling to−5° C., Et₃N (11.1 g, 0.110 mol) was added slowly over 30 min (internaltemperature <3° C.). The reaction was allowed to warm to RT and stirredfor 1 h (reaction monitored by analytical HPLC), at which point startingmaterial had been consumed. The reaction was washed with aqueous HCl(2×50 mL of a 3N solution). The combined aqueous layers were extractedwith CH₂Cl₂ (50 mL). The combined organic extracts were successivelywashed with satd. aqueous NaHCO₃ and brine (50 mL each), dried (Na₂SO₄),and concentrated to ˜30 mL volume. Methyl tert-butyl ether (120 mL) wasadded and the mixture was stirred; a white solid was formed. The mixturewas cooled to −20° C. for complete crystallization. The product wasfiltered and vacuum-dried to give Part A compound (23.3 g, 85%) as awhite solid. The mother liquor was concentrated in vacuo andrecrystallized from methyl tert butyl ether/heptane to give a secondcrop of Part A compound (3.3 g, 12%; total yield=97%).

To a −78° C. solution of ethyl propynoate (10.0 g; 100 mmol) inanhydrous THF (200 mL) was added dropwise n-BuLi (40 mL of a 2.5 Msolution in hexane; 100 mmol) over 30 min. The reaction was stirred at−78° C. for 30 min, after which a solution of 4-benzyloxybenzaldehyde(21.0 g; 100 mmol) in THF (100 mL) was added dropwise. The reaction wasstirred at −78° C. for 1 h, excess saturated aqueous NH₄Cl wascautiously added to quench the reaction, and the mixture was allowed towarm to RT. Volatiles were removed in vacuo and the residue waspartitioned between EtOAc and saturated aqueous NH₄Cl. The organic phasewas dried (Na₂SO₄) and concentrated in vacuo; the residue waschromatographed (SiO₂; continuous gradient from 100% hex to 100% EtOAcover 50 min) to give Part B compound (7.0 g; 23%) as an oil.

[M+H]⁺=311; ¹H NMR (CDCl₃) δ 7.35 (m, 7H), 6.95 (d, J=8.4 Hz, 2H), 5.47(d, J=6 Hz, 1 h), 5.05 (s, 2H), 4.20 (q, J=7.2 Hz, 2H), 1.27 (t, J=7.2Hz, 3H). ¹³C NMR (CDCl₃) δ 159.6, 137.4, 131.6, 129.0, 128.6, 128.4,127.8, 115.6, 87.3, 78.2, 70.5, 64.3, 62.6, 14.4.

To a 0° C. solution of Part B compound (4.50 g; 14.5 mmol) in CH₂Cl₂ (50mL) were successively added pyridine (1.80 mL; 22.3 mmol) and acetylchloride (1.30 mL; 18.1 mmol). The reaction was stirred at 0° C. for 2h, then was partitioned between CH₂Cl₂ and 5% aqueous HCl. The organicphase was washed with brine, dried (MgSO₄) and concentrated in vacuo togive Part C compound (5.0 g; 95%) as an oil.

[M+H]⁺=353; ¹H NMR (CDCl₃) δ 7.40 (m, 7H), 6.98 (d, 2H), 6.47 (s, 1H),5.07 (s, 2H), 4.24 (q, J=7.2 Hz, 2H), 2.08 (s, 3H), 1.30 (t, J=7.2 Hz,3H). ¹³C NMR (CDCl₃) δ 169.8, 160.1, 153.4, 137.0, 129.8, 129.0, 128.5,128.0, 127.8, 115.6, 83.4, 78.5, 70.5, 64.9, 62.6, 21.2, 14.5.

To a RT solution of Part C compound (1.0 g; 2.84 mmol) in toluene (2 mL)were successively added Example 1 Part B compound (900 mg; 3.8 mmol) andTFA (100 μL); a highly exothermic reaction occurred. The reaction wasstirred at RT for 2 h, then was concentrated in vacuo. The residue waschromatographed (SiO₂; continuous gradient from 100% hex to 100% EtOAcover 50 min) to give Part D compound (700 mg; 72%) as a light yellowoil.

[M+H]⁺=486; ¹H NMR (CDCl₃) δ 7.32 (m, 12H), 6.88 (d, J=8.4 Hz, 2H), 4.98(s, 2H), 4.15 (q, J=7.2 Hz, 2H), 3.66 (m, 6H), 2.01 (s, 3H), 1.19 (t,3H). ¹³C NMR (CDCl₃) δ 169.5, 163.3, 158.6, 150.8, 138.8, 136.8, 130.4,128.5, 128.5, 128.4, 127.9, 127.8, 127.4, 127.1, 114.8, 70.8, 70.0,60.5, 60.3, 60.0, 21.0, 14.2.

A mixture of Part D compound (700 mg; 1.44 mmol) and 10% Pd/C (100 mg)in HOAc (5 mL) and TFA (1 mL) was stirred under an atmosphere of H₂(balloon) for 48 h. The catalyst was filtered off on Celite® and thefiltrate was concentrated in vacuo. The crude product was dissolved inTHF (20 mL) and saturated aqueous NaHCO₃ (pH=9); di-tert butyldicarbonate (320 mg; 145 mmol) was added. The reaction was stirred at RTfor 2 h, then was concentrated in vacuo; the residue was partitionedbetween EtOAc and saturated aqueous NaHCO₃. The organic phase was washedwith brine, dried (MgSO₄) and concentrated in vacuo. The residue waschromatographed (SiO₂; continuous gradient from 100% hex to 100% EtOAcover 50 min) to give Part E compound (300 mg; 60%) as an oil.

A mixture of Part E compound (50 mg; 0.14 mmol), Part A compound (50 mg;0.17 mmol) and K₂CO₃ (23 mg; 0.17 mmol) in MeCN (5 mL) was stirred at85° C. for 18 h. The reaction was cooled to RT and volatiles wereremoved in vacuo and partitioned between EtOAc and saturated aqueousNH₄Cl. The organic phase was dried (MgSO₄) and concentrated in vacuo.The residue was chromatographed (SiO₂; continuous gradient from 100% hexto 100% EtOAc over 50 min) to give crude Part F compound.

An alternative procedure for the synthesis of Part F compound is asfollows:

To a RT solution of Part E compound (700 mg; 2.0 mmol) and5-phenyl-2-methyl-oxazole-4-ethanol (500 mg, 2.46 mol) in toluene (15mL) was added cyanomethylenetributylphosphine (500 μL; 2.0 mmol)dropwise. The mixture was heated at 88° C. in an oil bath for 2 h,cooled to RT and concentrated in vacuo. The residue was chromatographed(SiO₂; continuous gradient from 100% hex to 100% EtOAc over 50 min) togive Part F compound (800 mg; 75%). [M+H]⁺=536.6

A solution of crude Part F compound and LiOH.H₂O (25 mg; 0.61 mmol) inTHF (2 mL), MeOH (1 mL) and H₂O (0.3 mL) was stirred at 0° C. for 2 h,then was quenched with saturated aqueous NH₄Cl and concentrated invacuo. The residue was partitioned between saturated aqueous NH₄Cl andEtOAc. The organic phase was dried (Na₂SO₄) and concentrated in vacuo;the residue was purified by preparative HPLC (as described forExample 1) and lyophilized to give the title compound (5.0 mg; 7%) as asolid.

[M+H]⁺=507.4

¹H NMR (CD₃OD) δ 7.85 (m, 2H), 7.37 (m, 3H), 6.99 (d, 2H; J=8.4 Hz),6.77 (m, 2H), 4.13 (m, 2H), 3.51 (m, 1H), 3.35 (m, 1H), 3.15 (m, 2H),3.00 (m, 1H), 2.87 (t, 2H; J=8.4 Hz), 2.70 (m, 1H), 2.55 (m, 1H), 2.32(m, 1H), 2.27 (s, 2H), 1.35 (2S, 9H).In addition, a second, later eluting fraction from the preparative HPLCof the above crude product was identified as the epimerized trans-isomerExample 24 compound (5.0 mg; 7%):

[M+H]⁺=507.4

¹H NMR (CD₃OD) δ 7.94 (m, 2H), 7.4 (m, 3H), 7.09 (d, 2H; J=6.4 Hz), 6.84(d, J=8.0 Hz, 2H), 4.22 (m, 2H), 3.60 (m, 1H), 3.45 (m, 1H), 3.35 (m,1H), 3.05 (m, 1H), 2.95 (t, 2H; J=6.4 Hz), 1.80 (m, 2H), 2.60 (m, 2H),2.37 (s, 3H), 1.4 (s, 9H).

EXAMPLE 25

To a vigorously stirred mixture of chloroacetonitrile (7.5 g; 0.10 mmol)and hydroxylamine hydrochloride (6.95 g; 0.10 mmol) in H₂O (25 mL) wascarefully added Na₂CO₃ (5.3 g; 0.05 mmol) while maintaining the reactiontemperature at ≦30° C. The mixture was then stirred at 30° C. for 15min, then was extracted with Et₂O (2×80 mL). The combined organicextracts were dried (Na₂SO₄) and concentrated in vacuo to give Part Acompound (6.9 g; 64%) as a white solid.

To a 0° C. mixture of Part A compound (1.0 g; 9.0 mmol) and K₂CO₃ (870mg; 6.3 mmol) in acetone (45 mL) was added dropwise a solution ofbenzoyl chloride (1.0 mL; 9.0 mmol) in acetone (5 mL). The reaction wasallowed to warm to RT and stirred at RT for 30 min. Volatiles wereremoved in vacuo and the residue was partitioned between H₂O and EtOAc.The organic phase was washed with brine, dried (MgSO₄) and concentratedin vacuo to give crude Part B compound (1.50 g; 76%) as a white solid.

A solution of crude Part B compound (1.50 g) in HOAc (25 mL) was heatedto reflux for 1.5 h, after which volatiles were removed in vacuo. Theresidue was partitioned between H₂O (40 mL) and EtOAc (50 mL); theorganic phase was washed with H₂O (2×40 mL), saturated aqueous NaHCO₃(2×40 mL) and brine (40 mL), dried (MgSO₄) and concentrated in vacuo.The residue was chromatographed (SiO₂; continuous gradient from 4:1 to7:3 hexane:EtOAc) to give Part C compound (840 mg; 61%) as a whitesolid.

A mixture of crude Part C compound (120 mg; 0.60 mmol), Example 23 PartE compound (100 mg; 0.30 mmol) and K₂CO₃ (83 mg; 0.60 mmol) in MeCN (3mL) was heated at 90° C. for 8 h. After cooling to RT, the mixture wasfiltered. The filtrate was concentrated in vacuo and the residue waschromatographed (SiO₂; continuous gradient from 9:1 to 3:1 hex:EtOAc) togive Part D compound (140 mg; 96%) as a syrup. [M+H]⁺=508.3;[M+Na]⁺=530.3

A solution of Part D compound (140 mg; 0.28 mmol) and HCl (700 μL of a 4M solution in dioxane) in CH₂Cl₂ (5 mL) was stirred at RT for 2 h, thenwas concentrated in vacuo to give crude Part E compound (100 mg; 82%) asa white solid.

A solution of crude Part E compound (25 mg; 0.056 mmol), phenylchloroformate (9 μL; 0.067 mmol) and NaHCO₃ (24 mg; 0.28 mmol) in H₂Oand THF (2 mL each) was stirred at RT for 1 h, then was partitionedbetween H₂O and EtOAc (3 mL each). The organic phase was dried (MgSO₄)and concentrated in vacuo. The residue was chromatographed (SiO₂;continuous gradient from 9:1 to 3:1 hex:EtOAc) to give Part F compound(27 mg; 91%) as a white solid. [M+H]⁺=528.2

A solution of Part F compound (27 mg; 0.05 mmol) and LiOH.H₂O (11 mg;0.25 mmol) in THF and H₂O (1 mL each) was stirred at RT overnight, thenthe pH was adjusted to ˜3 with aqueous 1 N HCl. The mixture waspartitioned between H₂O and EtOAc. The organic phase was dried (Na₂SO₄)and concentrated in vacuo; the residue was purified by preparative HPLC(as described for Example 1 except that a continuous gradient from 1:1Solvent A:Solvent B to 100% B over 10 min was used, followed by 5 minhold at 100% B) to give two compounds. The compound with the shorterretention time was lyophilized from 1,4 dioxane to give the titlecompound (11 mg; 41%) as a white solid.

[M+H]⁺=500.0

¹H NMR (CD₃OD): δ 8.14 (m, 2H), 7.65 (m, 1H), 7.58 (m, 2H), 7.35 (m,2H), 7.20 (m, 3H), 7.08 (m, 2H), 7.03 (m, 2H), 5.24 (s, 2H), 3.90 (m,0.5H), 3.75 (m, 1H), 3.56 (m, 1H), 3.29-3.50 (m, 2.5H), 2.75-2.92 (m,2H), 2.54 (m, 1H)

The second compound (longer retention time) was determined to be thecorresponding epimerized trans-isomer. This compound was lyophilizedfrom dioxane to give Example 26 compound (6 mg; 23%) as a white solid.

EXAMPLE 26

[M+H]⁺=500.0

¹H NMR (CD₃OD): δ 8.14 (m, 2H), 7.65 (m, 1H), 7.58 (m, 2H), 7.35 (m,2H), 7.20 (m, 3H), 7.08 (m, 2H), 7.03 (m, 2H), 5.24 (s, 2H), 3.90 (m,0.5H), 3.75 (m, 1H), 3.65 (m, 1H), 3.50 (m, 0.5H), 3.32 (m, 0.5H), 3.22(m, 0.5H) 2.85-2.97 (m, 2H), 2.78 (m, 1H), 2.65 (m, 1H)

EXAMPLE 27

Example 25 Part E compound (25 mg; 0.056 mmol) and ethyl chloroformate(7 μL; 0.067 mmol) were reacted (using the same experimental procedureas for the preparation of Example 25 Part F compound) to give Part Acompound (20 mg; 74%) as a white solid. [M+H]⁺=480.21

A solution of Part A compound (20 mg; 0.042 mmol) and LiOH.H₂O (9 mg;0.21 mmol) in THF and H₂O (1 mL each) was stirred at RT overnight, afterwhich the pH was adjusted to ˜3 with aqueous 1 N HCl. The mixture waspartitioned between H₂O and EtOAc. The organic phase was dried (Na₂SO₄)and concentrated in vacuo; the residue was purified by preparative HPLC(as described for Example 25) to give two compounds. The compound withthe shorter retention time was lyophilized from 1,4 dioxane to give thetitle compound (9.3 mg; 49%) as a white solid.

[M+H]⁺=452.1

Analytical HPLC: retention time=4.91 min (YMC S5 ODS 4.6×50 mm column;continuous gradient from 50:50 A:B to 100% B over 8 min;A=90:10:0.1H₂O:MeOH:TFA; B=90:10:0.1 MeOH:H₂O:TFA; flow rate=2.5 mL/min)

¹H NMR (CD₃OD): δ 8.14 (m, 2H), 7.65 (m, 1H), 7.60 (m, 2H), 7.14 (m,2H), 7.01 (m, 2H), 5.24 (s, 2H), 4.10 (m, 2H), 3.68 (m, 1H), 3.50 (m,1H), 3.20-3.33 (m, 2H), 3.15 (m, 1H), 2.85 (m, 1H), 2.70 (m, 1H), 2.45(m, 1H), 1.22 (m, 3H)

The second compound (longer retention time) was determined to be thecorresponding epimerized trans-isomer. This compound was lyophilizedfrom dioxane to give Example 28 compound (3.2 mg; 17%) as a white solid.

EXAMPLE 28

[M+H]⁺=452.0

retention time=5.14 min (YMC S5 ODS 4.6×50 mm column; continuousgradient from 50:50 A:B to 100% B over 8 min; A=90:10:0.1H₂O:MeOH:TFA;B=90:10:0.1 MeOH:H₂O:TFA; flow rate=2.5 mL/min)

¹H NMR (CD₃OD): δ 8.14 (m, 2H), 7.67 (m, 1H), 7.59 (m, 2H), 7.16 (m,2H), 7.01 (m, 2H), 5.24 (s, 2H), 4.08 (m, 2H), 3.67 (m, 1H), 3.55 (m,1H), 3.42 (m, 1H), 3.10 (m, 1H), 2.90 (m, 1H), 2.82 (m, 1H), 2.68 (m,1H), 2.60 (m, 1H), 1.22 (m, 3H)

EXAMPLE 29

To a RT solution of L-(1R)-(+)-2,10-camphorsultam (1.0 g; 4.64 mmol) inanhydrous toluene (5 mL) under an atmosphere of N₂ was added Me₃Al (3.0mL of a 2.0 M solution in toluene; 6.0 mmol). The solution was stirredat RT for 2 h, after which Ph₃P═CHCO₂CH₃ (1.70 g; 5.0 mmol) was added.The reaction was stirred at 150° C. in a sealed tube for 2 h, cooled toRT, and partitioned between H₂O and EtOAc (50 mL each). The organicphase was washed with H₂O (2×50 mL), dried (Na₂SO₄) and concentrated invacuo. The residue was chromatographed (SiO₂; hexane:EtOAc 3:1) to givePart A compound (1.0 g; 39%) as an oil.

A solution of Part A compound (200 mg; 0.39 mmol) and the aldehyde(Example 1 Part E compound; 110 mg; 0.35 mmol) in toluene (20 mL) washeated at reflux for 2 h, then was concentrated in vacuo. The residuewas chromatographed (SiO₂; hex:EtOAc 3:1) to give Part B compound (51mg; 23%) as an oil.

To a solution of Part B compound (51 mg; 0.090 mmol) in toluene (2 mL)were successively added Example 1 Part B compound (36 mg; 0.15 mmol) anda catalytic amount of TFA (1 μL). The reaction was stirred at RT for 3h, then was partitioned between EtOAc (10 mL) and saturated aqueousNaHCO₃ (20 mL). The organic phase was dried (Na₂SO₄) and concentrated invacuo. The residue was chromatographed (SiO₂; hex:EtOAc 3:1) to providePart C compound (35 mg; 56%) as an oil.

A mixture of Part C compound (35 mg; 0.058 mmol) and 10% Pd/C (5 mg) inMeOH (5 mL) and HOAc (200 μL) was stirred under an atmosphere of H₂(balloon) for 5 h. Solids were removed by filtration through Celite® andthe filtrate was concentrated in vacuo to give Part D compound (25 mg;71%) as an oil.

A mixture of Part D compound (25 mg; 0.033 mmol), DMAP (13 mg; 0.1 mmol)and phenyl chloroformate (78 mg; 0.5 mmol) in CH₂Cl₂ (3 mL) was stirredat RT for 30 min, then was partitioned between EtOAc and H₂O (20 mLeach). The organic phase was washed with H₂O and aqueous 1 M HCl (10 mLeach), dried (Na₂SO₄) and concentrated in vacuo. The residue waschromatographed (SiO₂; continuous gradient from 100% hexane to 30:70hexane:EtOAc over 25 min) to give Part E compound (17 mg; 57%) as anoil.

A solution of Part A compound (17 mg; 0.024 mmol) in aqueous 1 N LiOH(0.5 mL; 0.50 mmol) and THF (1.5 mL) was stirred at RT for 6 h, then waspartitioned between aqueous 1 N HCl (1 mL) and EtOAc (2 mL). The organicphase was dried (Na₂SO₄) and concentrated in vacuo; the residue waspurified by preparative HPLC (as described for Example 25) to give thetitle compound (6 mg; 47%) as a white solid.

[M+H]⁺=527.0

EXAMPLE 30

D-(1S)-(−)-2,10-camphorsultam (1.0 g; 4.64 mmol) was reacted withPh₃P═CHCO₂CH₃ (1.70 g; 5.0 mmol) and Me3Al (3 mL of a 2 M solution intoluene) in exactly the same way as Example 29 Part A to give Part Acompound (1.0 g; 39%) as an oil.

Part A compound (200 mg; 0.39 mmol) was reacted with the aldehydeExample 1 Part E compound (110 mg; 0.35 mmol) in the same way as Example29 Part B to give Part B compound (45 mg; 20%) as an oil.

Part B compound (45 mg; 0.08 mmol) was reacted with Example 1 Part Bcompound (36 mg; 0.15 mmol) in the same way as Example 29 Part C to givePart C compound (28 mg; 51%) as an oil.

Part C compound (28 mg; 0.046 mmol) was used (the same procedure asdescribed in Example 29 Part D) to prepare Part D compound (20 mg; 72%)as an oil.

Part D compound (20 mg; 0.033 mmol) was reacted with phenylchloroformate (78 mg; 0.50 mmol) in the same manner as Example 29 Part Eto provide Part E compound (18 mg; 75%) as an oil.

Part E compound (18 mg; 0.025 mmol) was treated with aqueous LiOH (0.5mL of a 1 M solution) in the same manner as Example 29 Part F to providethe title compound (7 mg; 53%) as a solid.

[M+H]⁺=527.0

Example 31

To a RT solution of Example 23 Part F compound (30 mg; 0.056 mmol) inCH₂Cl₂ (1 mL) was added HCl (250 μL of a 4 M solution in dioxane). Thereaction was stirred at RT for 30 min, then was concentrated in vacuo togive crude Part A compound.

A mixture of crude Part A compound, ethyl chloroformate (50 μL; 0.52mmol), THF (5 mL) and saturated aqueous NaHCO₃ (sufficient to adjust thepH to ˜9) was stirred at RT for 30 min, then was concentrated in vacuo.The residue was partitioned between H₂O and Et₂O. The aqueous phase wasextracted with Et₂O; the combined organic extracts were dried (MgSO₄)and concentrated in vacuo to give crude Part B compound (25 mg; 76%) asan oil.

A mixture of Part B compound (5 mg; 0.01 mmol) in HOAc (500 μL) andaqueous HCl (150 μL of a 20% solution) was stirred at 80° C. for 18 h,then was cooled to RT and concentrated in vacuo. The residue waspartitioned between EtOAc and saturated aqueous NH₄Cl. The organic phasewas dried (Na₂SO₄) and concentrated in vacuo. The residue waslyophilized from dioxane to give the title compound (5 mg; 100%) as anoil.

[M+H]⁺=478.2

EXAMPLE 32

A mixture of 3-hydroxyphenyl ethanol (30.0 g; 0.217 mol), benzyl bromide(28.4 mL; 0.239 mol) and K₂CO₃ (45 g; 0.326 mol) in MeCN (500 mL) wasstirred at RT for 48 h, then was filtered. The filtrate was concentratedin vacuo; the residue was recrystallized from hexane to give Part Acompound (49 g; 99%) as a white solid.

To a mixture of Part A compound (40 g; 175 mmol) and Florisil (180 g) inCH₂Cl₂ (1 L) was added pyridinium chlorochromate (40 g; 186 mmol) inportions. The reaction was stirred at RT for 3.5 h, then was filteredthrough Florisil. To the filtrate was added more pyridiniumchlorochromate (20 g; 93 mmol) and Florisil (70 g). The reaction wasstirred at RT for another 2 h, then was filtered through Florisil. Thefiltrate was concentrated in vacuo to give crude Part B compound (34 g;86%) as an oil.

To a −78° C. solution of (CF₃CH₂O)₂POCH₂CO₂CH₃ (29.1 g; 91.5 mmol) and18-crown-6 (25 g; 95.4 mmol) in anhydrous THF (600 mL) under Ar wasadded dropwise KN(TMS)₂ (186 mL of a 1 M solution in toluene). Thereaction was stirred at −78° C. for 10 min, after which a solution ofPart B compound (17.3 g; 76.5 mmol) in THF (100 mL) was added dropwiseby cannula over 15 min. The reaction was stirred at −78° C. for 2 h,then was quenched by cautious slow addition of saturated aqueous NH₄Cl(150 mL). The mixture was allowed to warm to RT, then extracted withEtOAc. The organic phase was washed with H₂O (150 mL), dried (MgSO₄) andconcentrated in vacuo. The residue was chromatographed (SiO₂; stepwisegradient from 10:1 to 4:1 hex:EtOAc) to remove the crown ether. Thecrude product was chromatographed (SiO₂; continuous gradient from 10:1to 5:1 hex:EtOAc) to give Part C compound (6.5 g; 30%) as a pale yellowoil.

To a 0° C. solution of Part C compound (3.90 g; 13.8 mmol) and Example 1Part B compound (5.0 g; 20.7 mmol) in toluene (40 mL) was added TFA (200μL) dropwise. The reaction was stirred at 0° C. for 30 min, then waspartitioned between EtOAc (150 mL) and saturated aqueous NaHCO₃ (100mL). The organic phase was washed with brine (100 mL), dried (MgSO₄) andconcentrated in vacuo. The residue was chromatographed (SiO₂; continuousgradient from 4:1 to 1:1 hex:EtOAc) to give Part D compound (5.50 g;96%) as an oil.

A mixture of Part D compound (5.50 g; 13.3 mmol), 10% Pd/C (300 mg) andHOAc (1.13 mL; 20 mmol) in EtOH (100 mL) was stirred an atmosphere of H₂(balloon) for 26 h. The catalyst was filtered off (Celite®) and thefiltrate was concentrated in vacuo to give Part E compound (3.60 g; 92%)as an oil.

A mixture of Part E compound (3.60 g; 12.2 mmol), di-tert butyldicarbonate (2.66 g; 24.4 mmol) and NaHCO₃ (2.05 g; 24.4 mmol) in THFand H₂O (100 mL each) was stirred at RT for 1 h, then was partitionedbetween EtOAc (150 mL) and H₂O (100 mL). The organic phase was washedwith brine (100 mL), dried (MgSO₄) and concentrated in vacuo. Theresidue was chromatographed (SiO₂; continuous gradient from 4:1 to 3:2hex:EtOAc) to give Part F compound (3.70 g; 91%) as a syrup.

A mixture of Part F compound (150 mg; 0.43 mmol), Example 25 Part Ccompound (120 mg; 0.62 mmol), and K₂CO₃ (118 mg; 0.86 mmol) in MeCN (6mL) was heated at 80° C. for 16 h, then was cooled to RT and filtered.The filtrate was concentrated in vacuo and the residue waschromatographed (SiO₂; continuous gradient from 9:1 to 7:3 hex:EtOAc) togive Part G compound (200 mg; 94%) as a syrup.

A mixture of Part G compound (200 mg; 0.41 mmol) in HCl/dioxane (1.0 mLof a 4 M solution) and CH₂Cl₂ (4 mL) was stirred at RT for 1 h, then wasconcentrated in vacuo to give Part H compound (165 mg; 92%) as a whitesolid which was used in the next step without further purification.

A mixture of Part H compound (23 mg; 0.052 mmol), phenyl chloroformate(8 μL; 0.062 mmol) and NaHCO₃ (22 mg; 0.26 mmol) in THF and H₂O (1 mLeach) was stirred at RT for 1 h, then was partitioned between H₂O (5 mL)and EtOAc (10 mL). The organic phase was dried (MgSO₄) and concentratedin vacuo. The residue was purified by preparative HPLC (as described forExample 25) to give Part I compound (20 mg; 75%) as a colorless syrup.

A mixture of Part I compound (20 mg; 0.039 mmol) in conc. HCl (0.2 mL)and HOAc (1 mL) was heated at 70° C. for 18 h, then was cooled to RT andconcentrated in vacuo. The residue was purified by preparative HPLC (asdescribed for Example 25) and lyophilized from dioxane to give the titlecompound (10 mg; 51%) as a white solid.

[M+H]⁺=500.0

EXAMPLE 33

Example 32 Part H compound (23 mg; 0.052 mmol) and ethyl chloroformate(6 μL; 0.062 mmol) were reacted (using the same 2-step sequence asdescribed for the synthesis of Example 32) to give the title compound(7.7 mg; 33% for 2 steps) as a white solid.

[M+H]⁺=452.0

EXAMPLE 34

A mixture of 4-iodophenol (3.27 g; 14.9 mmol), K₂CO₃ (3 g; 21.7 mmol)and the mesylate Example 47 Part A compound (3.0 g; 10.7 mmol) in MeCN(50 mL) was heated at reflux overnight under N₂. The reaction was cooledto RT and partitioned between EtOAc and H₂O (200 mL each). The organicphase was washed with aqueous NaOH (2×20 mL of a 1 M solution) and H₂O,dried (Na₂SO₄) and concentrated in vacuo. The residue waschromatographed (SiO₂; continuous gradient from 100% hex to 7:3hex:EtOAc over 20 min, then at 7:3 hex:EtOAc for 15 min) to give Part Acompound (2.50 g; 57%) as a white solid.

A mixture of Part A compound (2.24 g; 5.53 mmol), Cu(I)I (42 mg; 0.221mmol), (Ph₃P)₂PdCl₂ (78 mg; 0.11 mmol), K₂CO₃ (3.05 g; 22.1 mmol) andtrimethylsilylacetylene (3.9 mL; 27.7 mmol) in THF (20 mL) was stirredat RT in a sealed tube for 60 h. The dark mixture was filtered, and thefiltrate was concentrated in vacuo. The residue was chromatographed(SiO₂; continuous gradient from 100% hex to 4:1 hex:EtOAc over 25 min,then at 4:1 hex:EtOAc for 10 min) to give Part B compound (2.04 g; 98%)as a brown solid.

A solution of Part B compound (2.04 g; 5.44 mmol) and tetrabutylammoniumfluoride (5.44 mL of a 1 M solution in THF) in THF (60 mL) was stirredat RT for 30 min, then was concentrated in vacuo. The residue waschromatographed (SiO₂; 100% hex to 3:1 hex:EtOAc) to give Part Ccompound (1.50 g; 91%) as a slightly yellow solid.

To a −78° C. solution of Part C compound (875 mg; 2.89 mmol) in THF (10mL) was added dropwise methyllithium (3.0 mL of a 1.4 M solution inEt₂O; 4.20 mmol). The reaction was stirred at −78° C. for 30 min, afterwhich dimethyl carbonate (900 μL; 10.6 mmol) was added dropwise.Stirring was continued at −78° C. for 30 min, after which the reactionwas allowed to warm to RT (30 min) and stirred at RT for 30 min. Excesssaturated aqueous NH₄Cl was added to quench the reaction and the mixturewas partitioned with EtOAc (150 mL). The organic phase was dried (MgSO₄)and concentrated in vacuo. The residue was chromatographed (SiO₂;gradient from 100% hex to 3:1 hex:EtOAc over 10 min; 3:1 hex:EtOAc for 5min, gradient from 3:1 to 2:1 hex:EtOAc over 5 min, then at 2:1hex:EtOAc for 10 min) to give Part D compound (800 mg; 77% as a whitesolid).

To a RT solution of Part D compound (700 mg; 2.2 mmol) in toluene (5 mL)were successively added TFA (100 μL) and Example 1 Part B compound (678mg; 2.86 mmol) over 2 min. The reaction was stirred at RT for 10 min,after which additional Example 1 Part B compound (290 mg; 1.23 mmol) wasadded over 15 min. A final aliquot of Example 1 Part B compound (290 mg;1.23 mmol) was added over 30 min. At this point (by analytical HPLC)there was 53% desired product, 15% of the bis-addition adduct and 12%unreacted starting material. The mixture was partitioned between EtOAcand saturated NaHCO₃ (20 mL each). The organic phase was concentrated invacuo and chromatographed (SiO₂; continuous gradient from 100% hex to85:15 hex:EtOAc over 15 min, 85:15 hex:EtOAc for 3 min, then continuousgradient from 85:15 to 3:2 hex:EtOAc over 5 min, then at 3:2 hex:EtOAcfor 5 min) to give Part E compound (596 mg; 62%) as an viscous oil.

To a −78° C. solution of Part E compound (122 mg; 0.247 mmol) in CH₂Cl₂(3 mL) was added CH₃CHClOCOCl (53 μL; 0.49 mmol) dropwise. The mixturewas stirred at −78° C. for 30 min, then was warmed to RT and stirred atRT for 3 h, then concentrated in vacuo. The residue was dissolved inMeOH (3 mL) and the mixture was stirred at RT for 72 h, thenconcentrated in vacuo to give crude Part F compound as a foam which wasused in the next step without further purification.

A mixture of crude Part F compound, NaHCO₃ (84 mg; 1.0 mmol) and di-tertbutyl dicarbonate (84 mg; 0.38 mmol) in THF/H₂O (3 mL of a 1:1 solution)was stirred at RT for 2 h, then was partitioned between EtOAc and H₂O(20 mL). The organic phase was concentrated in vacuo and the residue waschromatographed (SiO₂; continuous gradient from 100% hex to 85:15hex:EtOAc over 10 min, 85:15 hex:EtOAc for 3 min, 85:15 to 3:2 hex:EtOAcover 10 min and 3:2 hex:EtOAc for 5 min) to give Part G compound (55 mg;44% for 2 steps) as an oil. In addition Part E compound (30 mg; 25%) wasalso recovered.

A mixture of Part G compound (55 mg; 0.11 mmol) and LiOH.H₂O (10 mg;0.23 mmol) in THF/H₂O (1.6 mL of a 1:1 solution) was stirred at RT for16 h, after which the pH was adjusted to ˜5 by addition of aqueous 1 MHCl. The mixture was extracted with EtOAc (10 mL). The organic phase wasconcentrated in vacuo, and the residue was chromatographed (SiO₂; 3:1hex:EtOAc, then 100% EtOAc, then 10:1 EtOAc:MeOH) to give the titlecompound (45 mg; 80%) as a foam.

[M+H]⁺=491

EXAMPLE 35

A mixture of Example 34 Part E compound (20 mg; 0.040 mmol) and LiOH.H₂O(8 mg; 0.19 mmol) in THF/H₂O (1.6 mL of a 1:1 solution) was stirred atRT for 20 h, after which the pH was adjusted to ˜5 with aqueous 1 M HCl.The THF was removed in vacuo and the mixture was extracted with EtOAc(10 mL). The organic phase was concentrated in vacuo to give a whitesolid, which was further purified by crystallization from MeOH. Thismaterial was dissolved in CH₂Cl₂ (1 mL) and HCl in dioxane (4 drops of a4 N solution) was added. Volatiles were removed in vacuo to give thetitle compound (10 mg; 48%) as a white solid. [M+H]⁺=481

EXAMPLE 36

A mixture of 3-hydroxyphenylacetylene (1.0 g; 8.46 mmol), K₂CO₃ (4.0 g;30 mmol) and the mesylate Example 47 Part A compound (3.0 g; 10.7 mmol)in MeCN (10 mL) was heated at 90° C. for 5 h under N₂. The reaction wascooled to RT and the solids were filtered off; the filtrate waspartitioned between EtOAc and H₂O (100 mL each). The organic phase waswashed with aqueous HCl and NaOH (10 mL each of a 1 M solution), dried(Na₂SO₄) and concentrated in vacuo. The residue was chromatographed(SiO₂; 3:1 hex:EtOAc) to give Part A compound (1.25 g; 49%) as whitecrystals.

To a −78° C. solution of Part A compound (1.09 g; 3.59 mmol) inanhydrous THF (10 mL) was added methyllithium (3.2 mL of a 1.4 Msolution in Et₂O) dropwise. The reaction was stirred at −78° C. for 2 h,after which anhydrous dimethyl carbonate (1 mL; 12 mmol) was added inone portion. The reaction was allowed to warm to RT and stirred at RTfor 30 min, after which saturated aqueous NH₄Cl (5 mL) was added. Themixture was partitioned between EtOAc and H₂O (50 mL each). The organicphase was washed with H₂O (2×50 mL), dried (Na₂SO₄) and concentrated invacuo. The residue was chromatographed (SiO₂; 3:1 hexane:EtOAc) to givePart B compound (1.07 g; 83%) as an oil.

A mixture of Part B compound (1.07 g; 3.0 mmol), Example 17 Part Dcompound (0.79 g; 3.0 mmol) and TFA (1 drop) in toluene (10 mL) wasstirred at RT for 3 h, then was concentrated in vacuo. The residue waschromatographed (SiO₂; hex:EtOAc 1:1) to give Part C compound (1.01 g;64%) as white crystals.

A solution of Part C compound (500 mg; 0.953 mmol) in HOAc/concentratedHCl (5 mL of a 4:1 solution) was stirred at 66° C. for 30 h. Thereaction was cooled to RT and partitioned between ice water (100 mL) andEtOAc (20 mL). The aqueous phase was extracted with EtOAc (2×20 mL); thecombined organic extracts were washed with H₂O (2×50 mL), pH4 aqueousbuffer (50 mL), dried (Na₂SO₄), and concentrated in vacuo to a volume of˜5 mL. The precipitate was filtered off and dried in vacuo to give thetitle compound (310 mg; 63%) as a white solid.

[M+H]⁺=511.2

EXAMPLE 37

To a −78° C. solution of Example 36 Part C compound (474 mg; 0.90 mmol)in anhydrous CH₂Cl₂ (0.5 mL) was added CH₃CHClOCOCl (140 μL; 1.8 mmol)The reaction mixture was stirred at −78° C. for 30 min, then was warmedto −20° C. and stirred at −20° C. for 1 h. Volatiles were removed invacuo and MeOH (10 mL) was added; the solution was then stirred at RTfor 8 h. Volatiles were removed in vacuo to give crude Part A compound(450 mg; 99%) as an oil which was used in the next step without furtherpurification.

To a 0° C. solution of Part A compound (50 mg; 0.123 mmol) in THF (1 mL)was added saturated aqueous NaHCO₃ (1 mL), followed by ethylchloroformate (22 mg; 0.20 mmol). The reaction was stirred at 0° C. for15 min, then was partitioned between EtOAc and H₂O (5 mL each). Theorganic phase was washed with H₂O (5 mL), dried (MgSO₄) and concentratedin vacuo. A mixture of this crude carbamate-ester and aceticacid/concentrated HCl (4:1) was heated at 80° C. for 18 h; the reactionwas cooled to RT and concentrated in vacuo. The mixture was extractedwith EtOAc (10 mL). The organic phase was concentrated in vacuo, and theresidue was purified by preparative HPLC (as described for Example 1) togive the title compound (10 mg; 17%) as a white solid.

[M+H]⁺=463.2

EXAMPLE 38

The title compound (16 mg; 26%) was prepared from Example 37 Part Acompound (50 mg; 0.123 mmol) using the same sequence as for Example 37except that phenyl chloroformate (31 mg; 0.20 mmol) was used instead ofethyl chloroformate.

EXAMPLE 39

A suspension of Example 37 compound (5 mg; 0.011 mmol) and 10% Pd/C (5mg) in MeOH (2 mL) was stirred at RT under an atmosphere of H₂ (balloon)for 2 h. The catalyst was filtered off using Celite® and the filtratewas concentrated in vacuo. The residue was purified by preparative HPLC(as described for the purification of Example 1) to give the titlecompound (1.0 mg; 20%) as a white solid.

[M+H]⁺=465.2

EXAMPLE 40

The title compound (3.0 mg; 60%) was prepared from Example 38 compound(5 mg; 0.0098 mmol) according to the procedure described for thesynthesis of Example 39.

[M+H]⁺=513.2

EXAMPLE 41

To a −70° C. solution of Example 36 compound (500 mg; 0.952 mmol) inanhydrous THF (10 mL) was added dropwise DIBALH (2.4 mL of a 1 Msolution in hexane; 2.4 mmol). The reaction was stirred at −70° C. for20 min, then was warmed to RT and stirred at RT for 2 h, then cooled to−70° C. and finally quenched by dropwise addition of MeOH (1 mL). Themixture was allowed to warm to RT, then aqueous Rochelle salt (10 mL ofa 1 M solution) was added and stirring was continued for 1 h. Themixture was partitioned between H₂O and Et₂O (20 mL each). The aqueousphase was extracted with additional Et₂O (20 mL); the combined organicextracts were dried (Na₂SO₄) and concentrated in vacuo. The residue waschromatographed (SiO₂; EtOAc:hex:Et₃N 3:1:0.08) to give Part A compound(374 mg; 79%) as an oil.

To a −78° C. solution of Part A compound (261 mg; 0.53 mmol) in CH₂Cl₂(5 mL) was added CH₃CHClOCOCl (143 mg; 1.0 mmol). The reaction mixturewas stirred at −78° C. for 30 min, then was allowed to warm to RT andstirred at RT for 1 h. At this point, HPLC indicated that all startingmaterial had been consumed. Volatiles were removed in vacuo and MeOH (10mL) was added; the solution was then stirred at RT for 8 h. Volatileswere removed in vacuo to give crude Part B compound (100 mg; 51%) as anoil which was used in the next step without further purification.

A solution of crude Part B compound (100 mg; 0.27 mmol) and ethylchloroformate (47 μL; 0.50 mmol) in saturated aqueous NaHCO₃ (2 mL) andTHF (1 mL) was stirred at 0° C. for 15 min, then was partitioned betweenH₂O and EtOAC (5 mL each). The organic phase was washed with H₂O (5 mL),dried (Na₂SO₄) and concentrated in vacuo. The residue was purified bypreparative HPLC (as described for the purification of Example 1) togive Part C compound (30 mg; 25%) as an oil.

To a 0° C. mixture of Part C compound (30 mg; 0.067 mmol) andpolyvinylpyridine (300 mg) in CH₂Cl₂ (1 mL) was added phosphorustribromide (134 μL of a 1 M solution in CH₂Cl₂; 0.134 mmol) dropwiseover 5 min. The reaction was allowed to warm to RT and stirred at RT for30 min, then was filtered. The filtrate was partitioned between CH₂Cl₂(20 mL) and H₂O (50 mL). The organic phase was washed with saturatedaqueous NaHCO₃ (2×20 mL), dried (Na₂SO₄) and concentrated in vacuo. Theresidue was chromatographed (SiO₂; hex:EtOAc 3:1) to give Part Dcompound (13 mg; 38%) as an oil.

A mixture of Part D compound (13 mg; 0.025 mmol), (Ph₃P)₄Pd^(o) (5 mg;4.3×10⁻³ mmol) and KHCO₃ (100 mg; 1.0 mmol) in anhydrous MeOH (5 mL) inan autoclave was pressurized to 100 psi with carbon monoxide (flushed 3×with CO). The reaction mixture was stirred at RT for 3 days, after whichthe CO gas was released and the mixture was filtered. The filtrate wasconcentrated in vacuo and the residue was chromatographed (SiO₂; 3:1hex:EtOAc) to give Part E compound (9.3 mg; 76%) as an oil.

A mixture of Part E compound (9.3 mg; 0.019 mmol) and aqueous LiOH (0.5mL of a 1 N solution) in THF (1 mL) was stirred at RT for 2 h, afterwhich the reaction was partitioned between EtOAc (10 mL) and aqueous 1 MHCl (5 mL). The organic phase was washed with H₂O (3×10 mL) andconcentrated in vacuo. The residue was purified by preparative HPLC (asdescribed for Example 1) to give the title compound (8.3 mg; 92%) as anoil.

[M+H]⁺=477.2

EXAMPLE 42

A suspension of Example 41 compound (4 mg; 0.01 mmol) and 10% Pd/C (2mg) in MeOH (1 mL) was stirred at RT under an atmosphere of H₂ (balloon)for 2 h. The catalyst was filtered off on Celite® and the filtrate wasconcentrated in vacuo to give the title compound (3 mg; 60%) as a whitesolid.

[M+H]⁺=479.2

EXAMPLE 43

To a −78° C. solution of Example 34 Part G compound (420 mg; 0.833 mmol)in anhydrous THF (8 mL) under argon was added dropwise DIBALH (1.8 mL ofa 1 M solution in hexane; 1.8 mmol). The reaction was stirred at −78° C.for 5 min, then was allowed to warm to RT and stirred at RT for 30 min.Since starting material still remained, the reaction was cooled to −78°C. and more DIBALH (0.4 mL of a 1 M solution in hexane; 0.4 mmol) wasadded, after which the reaction was warmed to RT and stirred at RT for1.5 h. The reaction was cooled to −78° C. and MeOH (0.5 mL) was addeddropwise, followed by Rochelle's salt (2.35 g in 10 mL H₂O). The mixturewas allowed to warm to RT and stirred at RT for 1.5 h, after which EtOAc(20 mL) was added and stirring was continued for 10 min. The organicphase was concentrated in vacuo and chromatographed (SiO₂; 2:1 to 1:2hex:EtOAc, then 100% EtOAc) to give Part A compound (352 mg; 88%) as asolid foam.

To a RT solution of Part A compound (25 mg; 0.053 mmol) in CH₂Cl₂ (0.5mL) was added CCl₄ (35 mg; 0.228 mmol) and Ph₃P (24 mg; 0.092 mmol). Thereaction was stirred at RT overnight and concentrated in vacuo; theresidue was chromatographed (SiO₂; hex to 2:1 hex:EtOAc) to give Part Bcompound (10 mg; 38%) as an oil.

To a mixture of (Ph₃P)₄Pd^(o) (9 mg; 0.0078 mmol) and KHCO₃ (50 mg; 0.50mmol) in anhydrous MeOH (1 mL) was added a solution of Part C compound(10 mg; 0.020 mmol) 25 in EtOAc (0.8 mL). The reaction mixture was placein an autoclave and pressurized to 100 psi with carbon monoxide. Thereaction mixture was stirred at RT for 2 h, after which the CO gas wasreleased and the mixture was filtered. The filtrate was concentrated invacuo and the residue was chromatographed (SiO₂; 2:1 hex:EtOAc) to givePart C compound (8 mg; 76%) as an oil.

A solution of Part C compound (12 mg; 0.023 mmol) in TFA (0.2 mL) andCH₂Cl₂ (1 mL) was stirred at RT for 2.5 h, then was concentrated invacuo to give Part D compound as an oil, which was used in the next stepwithout further purification.

To a solution of Part D compound in THF (0.7 mL) was added a solution ofNaHCO₃ (8 mg; 0.095 mmol) in H₂O (0.7 mL), followed by ethylchloroformate (3 μL; 0.030 mmol). The reaction was stirred at RT for 2.5h, then partitioned between EtOAc and H₂O (10 mL each). The organicphase was dried (MgSO₄) and concentrated in vacuo. The residue waschromatographed (SiO₂; 2:1 hex:EtOAc) to give Part E compound (9.5 mg;84% for 2 steps) as an oil.

A mixture of Part E compound (9.5 mg; 0.019 mmol) and LiOH.H₂O (7 mg;0.17 mmol) in THF/H₂O (1.4 mL of a 1:1 solution) was stirred at RT for 2h, after which the pH was adjusted to ˜5 with aqueous 1 M HCl. Themixture was extracted with EtOAc (10 mL). The organic phase wasconcentrated in vacuo, and the residue was chromatographed (SiO₂; 1:1hex:EtOAc, 100% EtOAc, then 10:1 EtOAc:MeOH), then further purified bypreparative HPLC (conditions as described for Example 1 compound, exceptthat a continuous gradient from 30:70 A:B to 100% B over 10 min wasused) to give the title compound (4.2 mg; 46%) as a white foam.

[M+H]⁺=477

EXAMPLE 44

A mixture of Example 43 Part C compound (10 mg; 0.019 mmol) and LiOH.H₂O(2 mg; 0.048 mmol) in THF/H₂O (1.4 mL of a 1:1 solution) was stirred atRT for 16 h, after which the pH was adjusted to ˜5 with aqueous 1 M HCl.The mixture was extracted with EtOAc (10 mL). The organic phase wasconcentrated in vacuo, and the residue was chromatographed (SiO₂; 3:1hex:EtOAc, then 100% EtOAc, then 10:1 EtOAc:MeOH) to give the titlecompound (6 mg; 62%) as a foam.

[M+H]⁺=504.2

EXAMPLE 45

A mixture of Example 32 Part F compound (1.20 g; 3.6 mmol), K₂CO₃ (1.0g; 7.2 mmol) and 1,2 dibromoethane (3.1 mL; 36 mmol) in MeCN (50 mL) washeated at reflux for 46 h. Two additional portions of K₂CO₃ (0.5 g at 12& 36 h) were added during this time. The reaction was cooled to RT andfiltered; the filtrate was concentrated in vacuo. The residue waschromatographed (SiO₂; continuous gradient from 100% hex to 3:7hex:EtOAc) to give Part A compound (1.10 g; 70%) as a syrup.

A mixture of Part A compound (1.05 g; 2.4 mmol) and tetrabutylammoniumcyamide (1.27 g; 4.8 mmol) in CH₂Cl₂ (25 mL) was stirred at RT for 18 h,then was concentrated in vacuo. The residue was chromatographed (SiO₂;stepwise gradient from 4:1 to 3:2 hex:EtOAc) to give Part B compound(900 mg; 98%) as a syrup. [M+Na]⁺=411.2

A mixture of Part B compound (200 mg; 0.52 mmol), aqueous NH₂OH (136 mgof a 50% solution) in MeOH (6 mL) and H₂O (3 mL) was stirred at 95° C.for 3 h, then was cooled to RT and concentrated in vacuo. The residuewas partitioned between H₂O and EtOAc; the organic phase was dried(MgSO₄) and concentrated in vacuo to give crude Part C compound (200 mg;92%) as a white solid, which was used in the next step without furtherpurification. [M+H]⁺=422.3

A mixture of Part C compound (90 mg; 0.22 mmol) and benzoyl chloride (30μL; 0.26 mmol) in pyridine (5 mL) was stirred at reflux for 4 h, thenwas cooled to RT and concentrated in vacuo. The residue was partitionedbetween EtOAc (10 mL) and H₂O (5 mL); the organic phase was washed withbrine (5 mL), dried (MgSO₄) and concentrated in vacuo. The residue waschromatographed (SiO₂; continuous gradient from 9:1 to 5:1 hex:EtOAc) togive Part D compound (70 mg; 65%) as a syrup.

[M+H]⁺=508.3

A mixture of Part D compound (70 mg; 0.14 mmol) in HCl/dioxane (1 mL ofa 4 M solution; 4.0 mmol) and CH₂Cl₂ (3 mL) was stirred at RT for 2.5 h,then was concentrated in vacuo to give Part E compound (50 mg; 79%),which was used in the next step without further purification.

A mixture of Part E compound (25 mg; 0.055 mmol), phenyl chloroformate(8 μL; 0.11 mmol) and NaHCO₃ (23 mg; 0.28 mmol) in THF/H₂O (2 mL of a1:1 solution) was stirred at RT for 1 h, then was partitioned betweenEtOAc and H₂O (5 mL each). The organic phase was dried (MgSO₄) andconcentrated in vacuo. The residue was purified by preparative HPLC (asdescribed for the purification of Example 26) to give Part F compound(19 mg; 66%) as a syrup. [M+H]⁺=528.2

A mixture of Part F compound (19 mg; 0.036 mmol) in concentratedHCl/glacial HOAc (2 mL of a 1:4 solution) was stirred at 70° C. for 16h, then was cooled to RT and concentrated in vacuo. The residue waspurified by preparative HPLC (as described for the purification of PartF compound) and lyophilized from dioxane to give the title compound (17mg; 92%) as a white solid.

[M+H]⁺=514.2

EXAMPLE 46

A mixture of Example 45 Part E compound (25 mg; 0.055 mmol), phenylchloroformate (6 μL; 0.11 mmol) and NaHCO₃ (23 mg; 0.28 mmol) in THF/H₂O(2 mL of a 1:1 solution) was stirred at RT for 1 h, then was partitionedbetween EtOAc and H₂O (5 mL each). The organic phase was dried (MgSO₄)and concentrated in vacuo. The residue was purified by preparative HPLC(as described for the purification of Example 26) to give Part Acompound (18 mg; 69%) as a syrup. [M+H]⁺=480.2

A mixture of Part A compound (18 mg; 0.038 mmol) in concentratedHCl/glacial HOAc (2 mL of a 1:4 solution) was stirred at 70° C. for 16h, then was cooled to RT and concentrated in vacuo. The residue waspurified by preparative HPLC (as described for the purification of PartF compound) and lyophilized from dioxane to give the title compound (17mg; 97%) as a white solid.

[M+H]⁺=466.2

EXAMPLE 47

To a −5° C. solution of 5-phenyl-2-methyl-oxazole-4-ethanol (20.0 g,0.098 mol) in CH₂Cl₂ (100 mL) was added methanesulfonyl chloride (12.40g, 0.108 mol) in one portion (exothermic reaction). After recooling to−5° C., Et₃N (11.1 g, 0.110 mol) was added slowly over 30 min (internaltemperature <3° C.). The reaction was allowed to warm to RT and stirredfor 1 h (reaction monitored by analytical HPLC), at which point startingmaterial had been consumed. The reaction was washed with aqueous HCl(2×50 mL of a 3N solution). The combined aqueous layers were extractedwith CH₂Cl₂ (50 mL). The combined organic extracts were successivelywashed with satd. aqueous NaHCO₃ and brine (50 mL each), dried (Na₂SO₄),and concentrated to ˜30 mL volume. Methyl tert-butyl ether (120 mL) wasadded and the mixture was stirred; a white solid was formed. The mixturewas cooled to −20° C. for complete crystallization. The product wasfiltered and vacuum-dried to give the product mesylate (23.3 g, 85%) asa white solid. The mother liquor was concentrated in vacuo andrecrystallized from methyl tert butyl ether/heptane to give a secondcrop of product mesylate (3.3 g, 12%; total yield=97%).

A mixture of Part A compound (13.6 g, 0.048 mol), 4-hydroxybenzaldehyde(7.09 g, 0.058 mol) and K₂CO₃ (9.95 g, 0.072 mol) in DMF (110 mL) washeated at 100° C. for 2 h (reaction complete by analytical HPLC). Themixture was allowed to cool to RT and then poured into ice-water (400mL) and stirred for 30 min. The solid product was filtered and washedwith cold water (3×25 mL) and dried in vacuo at 50°-60° C. overnight.The crude product was crystallized from MTBE-Hexane to give (12.2 g,82%; 2 crops) Part B compound as a white solid.

To a RT solution of Part B compound (2.70 g; 8.80 mmol), ethyltrimethylsilylpropynoate (2.0 mL; 10.5 mmol) in CH₂Cl₂ (40 mL) was addedKF (570 mg; 9.8 mmol) and catalytic 18-crown-6 (50 mg; 0.20 mmol). Thereaction mixture was stirred at 45° C. for 18 h, at which point thereaction was complete by analytical HPLC. The reaction was extractedwith aqueous 1 N HCl, dried (Na₂SO₄) and concentrated in vacuo. MeOH (50mL) and TFA (2 mL) were added and the mixture was stirred at RT for 4 h,then concentrated in vacuo and partitioned between Et₂O and saturatedaqueous NaHCO₃. The organic phase was dried (Na₂SO₄) and concentrated invacuo to give Part C compound (3.50 g; 90%) which was used in the nextstep without further purification.

To a 0° C. solution of Part C compound (3.50 g; 8.6 mmol) in CH₂Cl₂ (20mL) were successively added pyridine (1.0 mL; 12.3 mmol) and acetylchloride (0.8 mL; 11.2 mmol). The reaction was stirred at 0° C. for 30min, then extracted with aqueous 10% HCl and saturated aqueous NaHCO₃.The organic phase was dried (MgSO₄) and concentrated in vacuo to givePart D compound (4.0 g; 98%) as an oil which was used in the next stepwithout further purification.

To a RT solution of Part D compound (4.0 g; 8.9 mmol) and Example 1 PartB compound (3.0 g; 12.6 mmol) in toluene (15 mL) was slowly added TFA(100 μL). An exothermic reaction ensued, and the reaction was stirred atRT for 3 h, then was concentrated in vacuo. The residue waschromatographed (SiO₂; continuous gradient from 100% hex to 100% EtOAc)to give Part E compound (2.5 g; 48%) as an oil.

A mixture of Part E compound (2.50 g; 4.3 mmol) and 10% Pd/C (500 mg) inglacial HOAc (20 mL) was stirred under an atmosphere of H₂ (65 psi) in apressurized vessel for 48 h. The catalyst was filtered off and thefiltrate was concentrated in vacuo. The residue was partitioned betweenEtOAc and saturated aqueous NaHCO₃. The organic phase was dried (Na₂SO₄)and concentrated in vacuo to give Part F compound (1.70 g; 90%; aceticacid salt) as an oil.

G.

A mixture of Part F compound (25 mg; 0.057 mmol), 2-chlorobenzoxazole(10 mg; 0.065 mmol) and Et₃N (20 μL; 0.14 mmol) in toluene (1 mL) wasstirred at 120° C. in a sealed tube for 3 h, then was cooled to RT andconcentrated in vacuo. The residue was partitioned between Et₂O andsaturated aqueous NaHCO₃; the organic phase was dried (MgSO₄) andconcentrated in vacuo. The residue was chromatographed (SiO₂; continuousgradient from 100% hex to 100% EtOAc) to give Part G compound (20 mg;63%) as an oil.

A mixture of Part G compound (10 mg; 0.018 mmol) in glacial HOAc (1 mL)and 20% aqueous HCl (0.25 mL) was heated at 80° C. for 18 h, then wascooled to RT and concentrated in vacuo. The residue was partitionedbetween CH₂Cl₂ and saturated aqueous NH₄Cl. The organic phase was dried(Na₂SO₄) and concentrated in vacuo; the residue was purified bypreparative HPLC (as described for the purification of Example 26) andlyophilized from H₂O to give the title compound (5 mg; 55%) as a whitesolid.

[M+H]⁺=524.6

¹H NMR (CD₃OD) δ 7.85 (m, 2H), 7.37 (m, 4H), 7.20 (m, 2H), 7.07 (m, 3H),6.79 (d, J=8.8 Hz, 2H), 4.12 (t, J=6.4 Hz, 2H), 3.95 (m, 1 h), 3.80 (m,1H), 3.55 (m, 1H), 3.45 (m, 1H), 3.30 (m, 1H), 2.87 (m, 4H), 2.45 (m,1H).

EXAMPLE 48

A mixture of Example 47 Part F compound (17 mg; 0.039 mmol) and2-chloro-pyrimidine (25 mg; 0.22 mmol) and Et₃N (30 μL; 0.22 mmol) washeated in a sealed tube at 130° C. for 3 h, then was cooled to RT andconcentrated in vacuo. The residue was partitioned between Et₂O andsaturated aqueous NaHCO₃ (20 mL each). The organic phase was dried(MgSO₄) and concentrated in vacuo to give crude Part A compound, whichwas used in the next step without further purification.

A mixture of crude Part A compound in glacial HOAc (1 mL) and 20%aqueous HCl (0.25 mL) was stirred at 85° C. for 18 h, then was cooled toRT and concentrated in vacuo. The residue was partitioned between CH₂Cl₂and saturated aqueous NH₄Cl. The organic phase was dried (Na₂SO₄) andconcentrated in vacuo; the residue was purified by preparative HPLC (asdescribed for the purification of Example 1 except that an 8 mingradient was employed instead of a 10 min gradient) and lyophilized fromH₂O to give the title compound (10 mg; 50%) as a brown solid.

[M+H]⁺=485.2

EXAMPLE 49

The title compound (1.2 mg; 4%) was prepared from Example 47 Part Fcompound (25 mg; 0.058 mmol) and 2,4-dichloro-pyrimidine (10 mg; 0.067mmol) using the same procedure as for the preparation of Example 48.

[M+H]⁺=501.2

Also recovered was 0.8 mg (3%) of the regioisomeric product Example 49Acompound

EXAMPLE 49A COMPOUND

[M+H]⁺=501.2

EXAMPLE 50

The title compound (15 mg; 50%) was prepared from Example 47 Part Fcompound (25 mg; 0.057 mol) and 2-chloro-4-trifluoromethyl-pyrimidine(10 mg; 0.054 mmol) using the same sequence as described for thesynthesis of Example 48.

[M+H]⁺=553.2

EXAMPLE 51

A mixture of Example 23 Part E compound (1.05 g; 3.0 mmol), K₂CO₃ (1.66g; 12 mmol) and 1,2 dibromoethane (2.6 mL; 30 mmol) in MeCN (25 mL) washeated at reflux for 40 h. Two additional portions of K₂CO₃ (1.5 g at 12and 36 h) were added during this time. The reaction was cooled to RT andfiltered; the filtrate was concentrated in vacuo. The residue waschromatographed (SiO₂; stepwise gradient from 9:1 to 3:1 hex:EtOAc) togive Part A compound (1.05 g; 76%) as a syrup.

A mixture of Part A compound (1.04 g; 2.3 mmol) and tetrabutylammoniumcyamide (1.23 g; 4.6 mmol) in CH₂Cl₂ (10 mL) was stirred at RT for 64 h,then was concentrated in vacuo. The residue was chromatographed (SiO₂;stepwise gradient from 9:1 to 7:3 hex:EtOAc) to give Part B compound(860 mg; 94%) as a syrup. [M+H]⁺=403.4

A mixture of Part B compound (160 mg; 0.40 mmol), aqueous NH₂OH (105 mgof a 50% solution) in MeOH (4 mL) and H₂O (2 mL) was stirred at 95° C.for 3 h, then was cooled to RT and concentrated in vacuo. The residuewas partitioned between H₂O and EtOAc; the organic phase was dried(MgSO₄) and concentrated in vacuo to give crude Part C compound (165 mg;95%) as a white solid, which was used in the next step without furtherpurification. [M+H]⁺=436.4

A mixture of Part C compound (95 mg; 0.22 mmol) and benzoyl chloride (30μL; 0.26 mmol) in pyridine (5 mL) was stirred at 130° C. for 4 h, thenwas cooled to RT and concentrated in vacuo. The residue was partitionedbetween EtOAc and aqueous 1 M HCl (4 mL each); the organic phase waswashed with brine (4 mL), dried (MgSO₄) and concentrated in vacuo. Theresidue was chromatographed (SiO₂; stepwise gradient from 9:1 to 4:1hex:EtOAc) to give Part D compound (85 mg; 75%) as a syrup. [M+H]⁺=522.4

A mixture of Part D compound (85 mg; 0.16 mmol) in HCl/dioxane (0.6 mLof a 4 M solution; 2.4 mmol) and CH₂Cl₂ (3 mL) was stirred at RT for 2h, then was concentrated in vacuo to give Part E compound (75 mg; 100%)as a white solid, which was used in the next step without furtherpurification.

A mixture of Part E compound (25 mg; 0.055 mmol), phenyl chloroformate(8 μL; 0.11 mmol) and NaHCO₃ (23 mg; 0.28 mmol) in THF/H₂O (2 mL of a1:1 solution) was stirred at RT for 1 h, then was partitioned betweenEtOAc and H₂O (4 mL each). The organic phase was dried (MgSO₄) andconcentrated in vacuo. The residue was purified by preparative HPLC (asdescribed for the purification of Example 26) to give Part F compound(21 mg; 71%) as a solid.

A mixture of Part F compound (21 mg; 0.039 mmol) in concentratedHCl/glacial HOAc (2.4 mL of a 1:5 solution) was stirred at 70° C. for 16h, then was cooled to RT and concentrated in vacuo. The residue waspurified by preparative HPLC (as described for the purification of PartF compound) and lyophilized from dioxane to give the title compound (14mg; 70%) as a white solid.

[M+H]⁺=514.2

EXAMPLE 52

The 2-step sequence used to synthesize Example 51 from Example 51 Part Ecompound was also used to prepare the title compound (15 mg; 59% for 2steps) from Example 51 Part E compound (25 mg; 0.055 mmol) and ethylchloroformate (6 μL; 0.066 mmol).

[M+H]⁺=466.2

EXAMPLE 53

The 2-step sequence used to synthesize Example 51 from Example 51 Part Ecompound was also used to prepare the title compound (15 mg; 52% for 2steps) from Example 51 Part E compound (25 mg; 0.055 mmol) and isobutylchloroformate (9 μL; 0.066 mmol).

[M+H]⁺=494.2

EXAMPLE 54

A mixture of methyl 4-chloroacetoacetate (400 mg; 2.6 mmol) and sodiumazide (136 mg; 2.1 mmol) in acetone (6 mL) was diluted with H₂O (˜1 mL)until the azide had dissolved. The mixture was heated at 50° C. for 1 h,stirred overnight at RT, then was heated at 50° C. for 2 h. The reactionwas cooled to RT and the acetone was removed in vacuo. The aqueous phasewas extracted with CH₂Cl₂; the combined organic extracts were dried(MgSO₄) and concentrated in vacuo. The residue was chromatographed(SiO₂; continuous gradient from 100% hex to 3:2 hex:EtOAc) to give PartA compound (237 mgs; 72%).

A mixture of Part A compound (237 mg; 1.51 mmol) and resin-bound Ph₃P(1.56 g of 3 mmol/g resin; 4.68 mmol) in dioxane (5 mL) was shaken for10 min at RT. Benzoyl chloride (263 mg; 1.87 mmol) was then added andthe reaction was heated at 75° C. for 2 h, then cooled to RT andfiltered. The filtrate was concentrated in vacuo and the residue waschromatographed (SiO₂; continuous gradient from 100% hex to 1:1hex:EtOAc; compound was pre-loaded onto the column with Celite®) to givePart B compound (95 mg; 28%) as a pale yellow oil.

A solution of LiAlH₄ in THF (2.0 mL of a 1 M solution; 2.0 mmol) wasadded dropwise to Part B compound (95 mg; 0.44 mol) at RT. The reactionwas stirred overnight at RT, then was cooled to 0° C. and quenchedcautiously with H₂O. Aqueous 3 N NaOH was added and the mixture wasconcentrated in vacuo. The residue was partitioned between CH₂Cl₂ andH₂O. The aqueous phase was extracted with CH₂Cl₂; the combined organicextracts were dried (Na₂SO₄) and concentrated in vacuo. The residue waschromatographed (SiO₂; continuous gradient from 100% hex to 100% EtOAc;compound preloaded onto column with CH₂Cl₂) to provide Part C compound(100 mg; 100%) as a colorless oil.

A RT mixture of Example 32 Part F compound (100 mg; 0.298 mmol) and 4 MHCl/dioxane (1 mL; 4 mmol) in CH₂Cl₂ (1 mL) was stirred at RT for 2 h,then was concentrated in vacuo. A mixture of the residue (crudepyrrolidine-phenol) and phenyl chloroformate (60 μL; 0.461 mmol) insaturated aqueous NaHCO₃ (1.5 mL) and THF (1 mL) was stirred at RTovernight, after which the THF was removed in vacuo. The aqueous phasewas extracted with CH₂Cl₂ (3×). The combined organic extracts were dried(MgSO₄) and concentrated in vacuo; the residue was chromatographed(SiO₂; continuous gradient from 100% hex to 100% EtOAc) to give Part Dcompound (110 mg; 100%) as a colorless oil.

A mixture of Part C compound (25 mg; 0.132 mmol), Part D compound (35mg; 0.098 mmol) and cyanomethylene tributylphosphorane (60 μL; 0.25mmol) in toluene (500 μL) at 70° C. was shaken overnight, then wasconcentrated in vacuo. The residue was chromatographed (SiO₂; continuousgradient from 100% hex to 2:3 hex:EtOAc) to give Part E compound (9 mg;contaminated with 50% Part D compound; 13%) as a yellow oil.[M+H]⁺=527.3

A mixture of Part E compound (4.5 mg; 0.008 mmol) in concentrated HCl(100 μL) and HOAc (400 μL) was heated at 70° C. for 24 h, then wascooled to RT and concentrated in vacuo. The residue was purified bypreparative HPLC (as for the purification of Example 26) to give thetitle compound (2 mg; 40%) as a solid.

[M+H]⁺=513.1

EXAMPLE 55

A RT mixture of Example 23 Part E compound (100 mg; 0.271 mmol) and 4 MHCl/dioxane (1 mL; 4 mmol) in CH₂Cl₂ (1 mL) was stirred at RT for 2 h,then was concentrated in vacuo. A mixture of the residue (crudepyrrolidine-phenol) and phenyl chloroformate (60 μL) in saturatedaqueous NaHCO₃ (1.5 mL) and THF (1 mL) was stirred at RT overnight, thenthe THF was removed in vacuo. The aqueous phase was extracted withCH₂Cl₂ (3×). The combined organic extracts were dried (MgSO₄) andconcentrated in vacuo; the residue was chromatographed (SiO₂; continuousgradient from 100% hex to 100% EtOAc) to give Part A compound (65 mg;62%) as a colorless oil.

A mixture of Example 54 Part C compound (25 mg; 0.132 mmol), Part Acompound (35 mg; 0.095 mmol) and cyanomethylene tributylphosphorane (60μL; 0.248 mmol) in toluene (500 μL) at 70° C. was shaken overnight, thenwas concentrated in vacuo. The residue was chromatographed (SiO₂;continuous gradient from 100% hex to 2:3 hex:EtOAc) to give Part Bcompound (30 mg; contaminated with 50% Part A compound; 43%) as a yellowoil. [M+H]⁺=541.4

A mixture of Part B compound (15 mg; 0.027 mmol) in concentrated HCl(100 μL) and HOAc (400 μL) was stirred at 70° C. for 24 h, then wascooled to RT and concentrated in vacuo. The residue was purified bypreparative HPLC (as for the purification of Example 26) to give thetitle compound (3 mg; 20%) as a solid.

[M+H]⁺=513.1

EXAMPLE 56

To a 0° C. solution of ethyl propionylacetate (10.0 g, 69.4 mmol) inCHCl₃ (60 mL) was added dropwise a solution of Br₂ (3.6 mL; 69.4 mmol)in CHCl₃ (20 mL) and the resulting mixture was stirred at 0° C. for 0.5h. The reaction was allowed to warm to RT and stirred at RT for 0.5 h.Air was then bubbled into the mixture for 1 h. Volatiles were thenremoved in vacuo to yield an oily residue to provide crude Part Acompound (15.3 g, >95% yield) as an oil which was used in the nextreaction without further purification.

A mixture of Part A compound (400 mg; 1.79 mmol) and sodium azide (136mg; 2.09 mmol) in acetone (6 mL) and H₂O (1 mL) was stirred at RT for 1h, then at 50° C. for 1 h. Analytical HPLC indicated that the startingmaterial had been consumed at this point. The acetone was removed invacuo and the aqueous phase was extracted with CH₂Cl₂. The combinedorganic extracts were dried (MgSO₄) and concentrated in vacuo; theresidue was chromatographed (SiO₂; continuous gradient from 100% hex to1:1 hex:EtOAc) to give Part B compound (280 mg; 85%) as a pale yellowoil.

A mixture of Part B compound (100 mg; 0.54 mmol) and resin-bound Ph₃P(540 mg of 3 mmol/g resin; 1.62 mmol) in dioxane (4 mL) was shaken for10 min at RT. Benzoyl chloride (84 mg; 0.60 mmol) was then added and thereaction was heated at 75° C. for 2 h, then cooled to RT and filtered.The filtrate was concentrated in vacuo and the residue waschromatographed (SiO₂; continuous gradient from 100% hex to 1:1hex:EtOAc; the compound was pre-loaded onto the column with Celite®) togive Part C compound (280 mg; 85%) as a pale yellow oil.

A solution of LiAlH₄ in THF (1 mL of a 1 M solution; 1 mmol) was addeddropwise to Part C compound (75 mg; 0.30 mol) at 0° C. The reaction waswarmed to RT and stirred overnight at RT, then was cooled to 0° C. andquenched cautiously with H₂O. Aqueous 3 N NaOH was added and the mixturewas concentrated in vacuo. The residue was partitioned between CH₂Cl₂and H₂O. The aqueous phase was extracted with CH₂Cl₂; the combinedorganic extracts were dried (Na₂SO₄) and concentrated in vacuo. Theresidue was chromatographed (SiO₂; continuous gradient from 100% hex to100% EtOAc; compound preloaded onto column with CH₂Cl₂) to provide PartD compound (55 mg; 89%) as a colorless oil.

A mixture of Part D compound (25 mg; 0.123 mmol), Example 54 Part Dcompound (35 mg; 0.098 mmol) and cyanomethylene tributylphosphorane (60μL; 0.248 mmol) in toluene (500 μL) at 70° C. was shaken overnight, thenwas concentrated in vacuo. The residue was chromatographed (SiO₂;continuous gradient from 100% hex to 2:3 hex:EtOAc) to give Part Ecompound (33 mg; contaminated with 10% Example 54 Part D compound; 60%)as a yellow oil.

[M+H]⁺=541.4

A mixture of Part E compound (16 mg; 0.031 mmol) in concentrated HCl(100 μL) and acetic acid (400 μL) was heated at 70° C. for 24 h, thenwas cooled to RT and concentrated in vacuo. The residue was purified bypreparative HPLC (as for the purification of Example 26) to give thetitle compound (7.5 mg; 45%) as a solid.

[M+H]⁺=527.1

EXAMPLE 57

A mixture of Example 56 Part D compound (25 mg; 0.123 mmol), Example 55Part A compound (35 mg; 0.095 mmol) and cyanomethylenetributylphosphorane (60 μL; 0.248 mmol) in toluene (500 μL) at 70° C.was shaken overnight, then was concentrated in vacuo. The residue waschromatographed (SiO₂; continuous gradient from 100% hex to 2:3hex:EtOAc) to give Part A compound (27 mg; contaminated with 12% Example56 Part D compound; 43%) as a yellow oil.

[M+H]⁺=555.4

A mixture of Part A compound (13 mg; 0.024 mmol) in concentrated HCl(100 μL) and HOAc (400 μL) was heated at 70° C. for 24 h, then wascooled to RT and concentrated in vacuo. The residue was purified bypreparative HPLC (as for the purification of Example 26) to give thetitle compound (7.5 mg; 60%) as a solid.

[M+H]⁺=527.1

EXAMPLE 58

To a solution of 4-formyl-2-phenylimidazole (100 mg, 0.58 mmol) inCH₂Cl₂ (2 mL) was added aqueous KOH (2 mL of a 30% solution), followedby dimethyl sulfate (66 μL, 0.70 mmol), and tetrabutylammonium bromide(10 mg; 0.039 mmol). The reaction mixture was stirred overnight at RTand then was partitioned between ETOAc and water; the organic phase waswashed with brine and then concentrated in vacuo. The residue waschromatographed (SiO₂; continuous gradient from 1:1 hexane:EtOAc to 100%EtOAc) to give 1-methyl-2-phenyl-imidazole-5-carboxaldehyde as a solid(35 mg; 32%; 1^(st) eluted fraction; Part A compound) and Part Bcompound

(45 mg; 42%; second eluted fraction) as a solid.

To a solution of Part A compound (50 mg, 0.27 mmol) in MeOH (2 mL) wasadded NaBH₄ (30 mg; 0.79 mmol). The mixture was stirred at RT for 1 h,after which the reaction was quenched with excess saturated aqueousNH₄Cl (1 mL). Volatiles were removed in vacuo, and the residue waspartitioned between saturated aqueous NaHCO₃ and EtOAc. The organicphase was washed with brine, dried (Na₂SO₄) and concentrated in vacuo togive Part C compound as a white solid (37 mg, 75%).

A mixture of Example 23 Part E compound (50 mg; 0.14 mmol), Part Ccompound (40 mg; 0.21 mmol) and cyanomethylene tributylphosphorane (50mg; 0.21 mmol) in toluene (1.5 mL) was stirred at 88° C. for 3 h, thenwas cooled to RT and concentrated in vacuo. The residue waschromatographed (SiO₂; continuous gradient from 3:2 to 1:4 hex:EtOAc) togive Part D compound (30 mg; 40%) as an oil.

A mixture of Part D compound (30 mg; 0.057 mmol) and LiOH.H₂O (30 mg;0.71 mmol) in MeOH (0.3 mL), THF (1 mL) and H₂O (0.5 mL) was stirred atRT for 1 h, after which saturated aqueous NH₄CL (1 mL) was added.Volatiles were removed in vacuo and the residue was partitioned betweenEtOAc and H₂O. The aqueous phase was extracted with EtOAc; the combinedorganic extracts were dried (Na₂SO₄) and concentrated in vacuo. Theresidue was purified by preparative HPLC (as for the purification ofExample 26 except that a continuous gradient from 40:60 A:B to 100% Bwas used) to give the title compound (5 mg; 17%) as a solid.

[M+H]⁺=527.1

In addition, the epimerized compound, Example 59, was also obtained (5mg; 17%) as a solid.

EXAMPLE 59

[M+H]⁺=527.1

EXAMPLE 60

HCl gas was bubbled through a solution of N-1-Boc-N-4-Fmoc-2-piperazinecarboxylic acid (5.0 g; 11 mmol) in MeOH (250 mL) at RT for 5 min. Thereaction was stirred at RT for 5 h, then was concentrated in vacuo. Theresidue was partitioned between EtOAc and 1N aqueous NaOH. The organicphase was dried (MgSO₄) and concentrated in vacuo to give Part Acompound (3.8 g; 95%) as an oil.

To a RT solution of Part A compound (1.0 g; 2.7 mmol) and the aldehydeExample 47 Part B compound (840 mg; 2.7 mmol)

in CH₂Cl₂ (150 mL) were successively added HOAc (1 mL) and NaBH(OAc)₃(930 mg; 4.7 mmol). The reaction was stirred at RT for 1 h and thenwashed with saturated aqueous NaHCO₃. The organic phase was dried(MgSO₄) and concentrated in vacuo to furnish Part B compound (1.74 g;97%) as an oil.

A solution of Part B compound (1.74 g; 2.65 mmol) and KOH (740 mg; 13.2mmol) in MeOH/H₂O (40 mL of a 1:1 solution) was stirred at RT for 18 h.Volatiles were removed in vacuo, and the residue was purified bypreparative HPLC (YMC reverse-phase ODS 30×250 mm column; detection at220 nm; flow rate=25 mL/min; continuous gradient from 100% A to 100% Bover 30 min+10 min hold time at 100% B, where A=90:10:0.1 H₂O:MeOH:TFAand B=90:10:0.1 MeOH:H₂O:TFA) to provide Part C compound (510 mg; 40%)as an oil.

To a RT solution of Part C compound (50 mg; 0.11 mmol) and4-chlorophenyl chloroformate (28 mg; 0.14 mmol) in CH₂Cl₂ (2 mL) wasadded Et₃N (70 μL; 0.52 mmol). The reaction was stirred at RT for 16 hand then was concentrated in vacuo. The residue was purified bypreparative HPLC (YMC reverse-phase ODS 20×100 mm column; detection at220 nm; flow rate=20 mL/min; continuous gradient from 100% A to 100% Bover 30 min+10 min hold time at 100% B, where A=90:10:0.1H₂O:MeOH:TFAand B=90:10:0.1 MeOH:H₂O:TFA) to provide the title compound (28 mg; 44%)as a solid.

[M+H]⁺=577.2

EXAMPLES 61-71

Examples 61 through 71 were prepared in a similar fashion to Example 60(from Example 60 Part C compound) using a variety of chloroformates.

Example # R [M + H]⁺ 61

542.1 62

572.3 63

577.4 64

618.1; 620.1 65

560.2 66

556.2 67

600.2 68

610.2 69

577.4 70

572.2 71

592.2

EXAMPLES 72-73

Examples 72 and 73 were prepared using an analogous synthetic sequenceto that used for the synthesis of Example 60. The only difference wasthat the aldehyde used was Example 436 Part A compound

instead of the aldehyde in Example 60.

Example # R [M + H]⁺ 72

542.4 73

572.2

EXAMPLES 74-88

Following the general sequence for the preparation of Example 45compound (using appropriately substituted benzoyl chlorides instead ofbenzoyl chloride), the following compounds of the invention wereprepared from Example 45 Part C compound.

Example No. R [M+ H]⁺ 74

528.4 75

582.4 76

544.4 77

528.5 78

582.4 79

598.4 80

544.4 81

558.4 82

550.4 83

528.5 84

570.5 85

582.4 86

598.4 87

544.4 88

548.4

EXAMPLE 89

To a solution of benzaldehyde (23.8 g, 234 mmol) in EtOAc (150 mL;pre-saturated with HCl gas) was added 2,3-butanedione mono-oxime (25.0g, 234 mmol) in one portion and the resulting solution was stirred at RTfor 12 h. Analytical HPLC indicated that all starting materials had beenconsumed. The reaction mixture was concentrated in vacuo to yield Part Acompound as a white solid, which was used in the next step withoutfurther purification.

To a solution of Part A compound in CHCl₃ (200 mL) was added dropwisePOCl₃ (30 mL, 320 mmol). The reaction was stirred for 12 h at 50° C.,then was concentrated in vacuo. The brown residue was partitionedbetween EtOAc (300 mL) and 1N aqeuous NaOH. The organic phase was washedwith brine, dried, (MgSO₄) and concentrated in vacuo. The residue waschromatographed (SiO₂; Et₂O) to give Part B compound (41.5 g; 86%) as alight brown solid (>95% pure by analytical HPLC and ¹H-NMR analysis).

A mixture of Example 23 Part E compound (140 mg; 0.4 mmol),

Part B compound (124 mg; 0.6 mmol) and K₂CO₃ (83 mg; 0.6 mmol) in CH₃CN(10 mL) was stirred at 95° C. for 2 h. The solids were filtered off, andthe filtrate was concentrated in vacuo. The residue was chromatographed(SiO₂; 9:1 to 4:1 hex:EtOAc) to give Part C compound (180 mg; 86%) as anoil.

To a solution of Part C compound (180 mg; 0.35 mmol) in CH₂Cl₂ (5 mL)was added HCl in dioxane (0.5 mL of a 4M solution; 2 mmol). The reactionwas stirred at RT for 2 h, then was concentrated in vacuo to give crudePart D compound (152 mg; 96%) as a white solid, which was used in thenext reaction without further purification.

A solution of Part D compound (25 mg; 0.055 mmol), isobutylchloroformate (11 μL; 0.083 mmol) and NaHCO₃ (18 mg; 0.22 mmol) in 1:1THF:H₂O (3 mL) was stirred at RT for 30 min, then was partitionedbetween EtOAc and H₂O. The organic phase was dried (MgSO₄) andconcentrated in vacuo. The residue was purified by preparative HPLC (YMCreverse-phase ODS 20×100 mm column; detection at 220 nm; flow rate=20mL/min; continuous gradient from 50% A to 100% B over 10 min+3 min holdtime at 100% B, where A=90:10:0.1H₂O:MeOH:TFA and B=90:10:0.1MeOH:H₂O:TFA) to give Part E compound (20 mg; 70%) as an oil.

A solution of Part E compound (20 mg; 0.04 mmol) and LiOH (6 mg; 0.16mmol) in THF/H₂O (2 mL of a 1:1 solution) was stirred at RT for 18 h.The reaction was acidified to pH 3 with 1 M aqueous HCl and extractedwith EtOAc (2×). The combined organic extracts were dried (Na₂SO₄) andconcentrated in vacuo. The residue was purified by preparative HPLC (YMCreverse-phase ODS 20×100 mm column; detection at 220 nm; flow rate=20mL/min; continuous gradient from 50% A to 100% B over 10 min+3 min holdtime at 100% B, where A=90:10:0.1H₂O:MeOH:TFA and B=90:10:0.1MeOH:H₂O:TFA) to give the title compound as a white solid (7.3 mg; 39%).[M+H]⁺=493.5

In addition, a second fraction from the preparative HPLC of the abovecrude product was identified as the epimerized trans-isomer Example 90compound (white solid; 3.6 mg; 19%).

[M+H]⁺=493.5

EXAMPLES 91-94

Following the general procedure for the synthesis of Examples 89 and 90,the following compounds (Examples 91-94) of the invention were prepared:Example No. Structure [M + H]⁺ 91

465.5 92

465.5 93

513.5 94

513.5

EXAMPLES 95-97

Following the general procedure for the synthesis of Example 89, exceptthat Example 32 Part F compound (the methyl ester)

was used instead of Example 23 Part E compound (the ethyl ester), thefollowing compounds of the invention were prepared: Ex- am- [M + pleStructure H]⁺ 95

465.5 96

493.5 97

513.5

EXAMPLE 98

A mixture of Example 32 Part F compound (600 mg; 1.8 mmol), K₂CO₃ (1.2;9.0 mmol)

and α-chloroacetonitrile (0.6 mL; 9.0 mmol) in CH₃CN (10 mL) was heatedat 95° C. for 3 h. Solids were filtered off, and the filtrate wasconcentrated in vacuo. The residue was chromatographed (SiO₂, 4:1 to 7:3hex:EtOAc) to give Part A compound as an oil (554 mg; 83%).

To a solution of Part A compound (554 mg; 1.5 mmol) in CH₂Cl₂ (5 mL) wasadded HCl in dioxane (1 mL of a 4 M solution; 4 mmol). The reactionmixture was stirred at RT for 3 h. Volatiles were removed in vacuo togive crude Part B compound (425 mg; 92% yield) as a white solid, whichwas used in the next reaction without further purification.

A solution of Part B compound (425 mg; 1.4 mmol), phenyl chloroformate(205 μL; 1.7 mmol) and NaHCO₃ (470 mg; 5.6 mmol) in THF/H₂O (10 mL of a1:1 solution) was stirred at RT for 1 h, then was partitioned betweenEtOAc and H₂O. The organic phase was washed with brine, dried (MgSO₄)and concentrated in vacuo. The residue was chromatographed (SiO₂; 4:1 to7:3 hex:EtOAc) to give Part C compound as an oil (500 mg; 93%).

A solution of Part C compound (500 mg; 1.3 mmol), and NH₂OH (420 mg; 3.3mmol) in MeOH (10 mL) and H₂O (5 mL) was stirred at 95° C. for 3 h.Volatiles were removed in vacuo, and the residue was lyophilized fromdioxane to give Part D compound (493 mg; 91%) as a solid, which was usedin the next reaction without further purification.

To a solution of Part D compound (25 mg; 0.06 mmol) in pyridine (1 mL)was added p-methyl benzoyl chloride (9 μL; 0.07 mmol). The reaction wasstirred at 115° C. for 4 h, then was cooled to RT and concentrated invacuo to give crude Part E compound, which was used in the next stepwithout further purification.

A solution of crude Part E compound and LiOH (9 mg; 0.2 mmol) in THF/H₂O(2 mL of a 1:1 solution) was stirred at RT for 18 h, then was acidifiedto pH 3 with excess 1M aqueous HCl. The aqueous phase was extracted withEtOAc (2×). The combined organic extracts were dried (MgSO₄) andconcentrated in vacuo. The residue was purified by preparative HPLC (YMCreverse-phase ODS 20×100 mm column; detection at 220 nm; flow rate=20mL/min; continuous gradient from 50% A to 100% B over 10 min+3 min holdtime at 100% B, where A=90:10:0.1H₂O:MeOH:TFA and B=90:10:0.1MeOH:H₂O:TFA) to give the title compound as a white solid (8.5 mg; 28%yield for 2 steps).

[M+H]⁺=514.6

EXAMPLES 99-105

Following the general procedure for the synthesis of Example 98, thefollowing compounds of the invention were prepared.

Example No. R [M + H]⁺ 99

530.6 100

544.5 101

556.6 102

558.6 103

584.5 104

584.5 105

530.6

EXAMPLE 106

To a −78° C. solution of methyl bis(trifluoroethyl) phosphonoacetate(1.3 g; 4.1 mmol) in dry THF (10 mL) under Ar was added NaH (141 mg of a60% dispersion in mineral oil; 3.6 mmol) in one portion, and the mixturewas stirred at −78° C. for 30 min. A solution of3-benzyloxy-benzaldehyde (500 mg; 2.4 mmol) in dry THF (5 mL) was thenadded dropwise and the reaction was stirred for 3 h at −78° C. Thereaction was then quenched by dropwise addition of saturated aqueousNH₄Cl, warmed to RT and partitioned between EtOAc and H₂O. The organicphase was washed with brine, dried (MgSO₄) and concentrated in vacuo.The residue was chromatographed (SiO₂; 100% hex to 85:15 hex:EtOAc) togive Part A compound (the desired cis isomer; 470 mg) as an oil.

In addition, Part B compound, the trans isomer (60 mg) was also obtainedas an oil.

The combined yield of both isomers was 96%.

To a solution of Part A compound (470 mg; 1.8 mmol), and Example 1 PartB compound (622 mg; 2.7 mmol) in toluene (15 mL) was added TFA (50 μL)dropwise. The mixture was stirred at RT for 1 h, then was partitionedbetween EtOAc and saturated aqueous NaHCO₃. The organic phase was dried(MgSO₄) and concentrated in vacuo. The residue was chromatographed(SiO₂; 100% hex to 7:3 hex:EtOAc) to give Part C compound (650 mg; 92%)as an oil.

To a 0° C. solution of Part C compound (600 mg; 1.5 mmol) in DCE (5 mL)was added dropwise 1-chloroethyl chloroformate (321 μL; 3.0 mmol) andthe reaction mixture was heated at 60° C. for 2 h. Volatiles wereremoved in vacuo, and the residue was dissolved in MeOH (5 mL) andheated at 600 for 1 h. Volatiles were removed in vacuo, and the residuewas lyophilized (dioxane) to give crude Part D compound (590 mg) as awhite solid, which was used in the next step without furtherpurification.

A solution of Part D compound (590 mg; 1.7 mmol), di-tert-butyldicarbonate (327 mg; 1.5 mmol), and NaHCO₃ (252 mg; 3.0 mmol) in THF/H₂O(10 mL of a 1:1 solution) was stirred at RT for 1 h, then waspartitioned between EtOAc and H₂O. The organic phase was washed withbrine, dried (MgSO₄), and concentrated in vacuo. The residue waschromatographed (SiO₂; 9:1 to 4:1 hex:EtOAc) to give Part E compound asan oil (530 mg; 86% yield for 2 steps).

To a −78° C. solution of Part E compound (530 mg; 1.3 mmol) in dry THF(5 mL) was added dropwise LiAlH₄ in THF (1.3 mL of a 1 M solution; 1.3mmol). The mixture was warmed to 0° C. and stirred at 0° C. for 30 min,then was cautiously quenched by dropwise addition of EtOAc and saturatedaqueous sodium potassium tartrate, and finally partitioned between EtOAcand H₂O. The organic phase was dried (MgSO₄) and concentrated in vacuo.The residue was chromatographed (SiO₂; 4:1 to 3:2 hex:EtOAc) to givePart F compound (390 mg; 79%) as an oil.

To a 0° C. solution of Part F compound (250 mg; 0.7 mmol), and Ph₃P (206mg; 0.8 mmol) in CH₂Cl₂ (4 mL) was added dropwise a solution of CBr₄(323 mg; 1.0 mmol) in CH₂Cl₂ (1 mL). The mixture was stirred at RT for 2h and then heated at reflux for 2 h. After cooling to RT, volatiles wereremoved in vacuo, and the residue was chromatographed (SiO₂, 9:1 to 7:3hex:EtOAc) to give Part G compound (169 mg; 70%).

A solution of Part G compound (169 mg; 0.4 mmol) and tetrabutylammoniumcyamide (406 mg; 1.6 mmol) in CH₂Cl₂ (10 mL) was stirred at RT for 18 h,then was heated to reflux for 2 h. Volatiles were removed in vacuo, andthe residue was chromatographed (SiO₂; 9:1 to 7:3 hex:EtOAc) to givePart H compound (45 mg; 65%).

A solution of Part H compound (2.9 g; 7.4 mmol) and 30% aqueous KOH (10mL) in MeOH (20 mL) was heated at 100° C. for 5 h, then was cooled toRT, acidified to pH 5 with aqueous 1M HCl and finally partitionedbetween EtOAc and H₂O. The organic phase was washed with brine, dried(MgSO₄) and concentrated in vacuo to give crude Part I compound (2.8 g;93%), which was used in the next reaction without further purification.

To a −78° C. solution of Part I compound (2.8 g; 6.9 mmol) in MeOH (30mL) was added dropwise a solution of TMSCHN₂ in hexane (17.1 mL of a 2 Msolution; 34.2 mmol), then was allowed to warm to RT and stirred at RTfor 5 h. Volatiles were removed in vacuo, and the residue waschromatographed (SiO₂; 100% hex to 3:7 hex:EtOAc) to give Part Jcompound (2.5 g; 86%) as an oil.

A mixture of Part J compound (1.0 g; 2.4 mmol), and 10% Pd/C (80 mg) inMeOH (30 mL) and glacial HOAc (5 drops) was stirred at RT for 4 h underan atmosphere of H₂ (balloon), then was neutralized with excess NaHCO₃and filtered. The filtrate was concentrated in vacuo to give Part Kcompound as an oil (730 mg; 93%).

A mixture of Part K compound (120 mg; 0.4 mmol), Example 25 Part Ccompound (116 mg; 0.6 mmol)

and K₂CO₃ (100 mg; 0.8 mmol) in CH₃CN (6 mL) was heated at 95° C. for 2h, then was cooled to RT. Solids were filtered off, and the filtrate wasconcentrated in vacuo. The residue was chromatographed (SiO₂; 95:5 to85:15 hex:EtOAc) to give Part L compound (160 mg; 91%) as an oil.

A solution of Part L compound (145 mg; 0.3 mmol) and HCl in dioxane (0.5mL of a 4M solution; 2.0 mmol) in CH₂Cl₂ (4 mL) was stirred at RT for 2h. Volatiles were removed in vacuo to give Part M compound (126 mg;100%) as a white solid

A solution of Part M compound (20 mg; 0.05 mmol), ethyl chloroformate (6μL, 0.07 mmol) and NaHCO₃ (16 mg; 0.2 mmol) in THF/H₂O (2 mL of a 1:1solution) was stirred at RT for 1 h, then was partitioned between EtOAcand H₂O. The organic phase was dried (MgSO₄) and concentrated in vacuoto give Part N compound, which was used in the next step without furtherpurification.

A solution of Part N compound and LiOH (10 mg; 0.24 mmol) in THF/H₂O (2mL of a 1:1 solution) was stirred at RT for 2 h, then was acidified topH 2 with aqueous 1 M HCl, and finally partitioned between EtOAc andH₂O. The organic phase was dried (MgSO₄) and concentrated in vacuo. Theresidue was purified by preparative HPLC (YMC reverse-phase ODS 20×100mm column; detection at 220 nm; flow rate=20 mL/min; continuous gradientfrom 50% A to 100% B over 10 min+4 min hold time at 100% B, whereA=90:0.1H₂O:MeOH:TFA and B=90:10:0.1 MeOH:H₂O:TFA) and lyophilized fromdioxane to furnish the title compound as a white solid (15 mg; 71%yield). [M+H]⁺=452.5

EXAMPLES 107-111

Following the procedure for the synthesis of Example 106, the followingcompounds of the invention were prepared. Example No. R [M + H]⁺ 107

466.5 108

480.5 109

500.5 110

530.6 111

480.5

EXAMPLE 112

A solution of Example 106 Part M compound (26 mg; 0.06 mmol),

2-chloro-4-(trifluoromethyl)pyrimidine (10 μL, 0.07 mmol) and Et₃N (21μL; 0.15 mmol) in toluene (5 mL) was heated at 80° C. for 30 min.Volatiles were removed in vacuo, and the residue was partitioned betweenEtOAc and H₂O. The organic phase was dried (MgSO₄) and concentrated invacuo to give crude Part A compound, which was used in the next stepwithout further purification.

A solution of crude Part A compound and LiOH (10 mg; 0.24 mmol) inTHF/H₂O (2 mL of a 1:1 solution) was stirred at RT for 2 h, then wasacidified to pH 2 with aqueous 1 M HCl, and finally partitioned betweenEtOAc and H₂O. The organic phase was dried (MgSO₄) and concentrated invacuo. The residue was purified by preparative HPLC (YMC reverse-phaseODS 20×100 mm column; detection at 220 nm; flow rate=20 mL/min;continuous gradient from 50% A to 100% B over 10 min+4 min hold time at100% B, where A=90:10:0.1H₂O:MeOH:TFA and B=90:10:0.1 MeOH:H₂O:TFA) andlyophilized from dioxane to furnish the title compound as a white solid(31 mg; 97%). [M+H]⁺=526.0

EXAMPLE 113

A mixture of Example 106 Part K compound (120 mg; 0.4 mmol),

Example 89 Part B compound (112 mg; 0.6 mmol)

and K₂CO₃ (100 mg; 0.8 mmol) in CH₃CN (6 mL) was heated at 95° C. for 2h, then cooled to RT. Solids were filtered off, and the filtrate wasconcentrated in vacuo. The residue was chromatographed (SiO₂; 95:5 to85:15 hex:EtOAc) to give Part A compound (145 mg; 80%) as an oil.

A solution of Part A compound (133 mg; 0.3 mmol) and HCl in dioxane (0.5mL of a 4M solution; 2.0 mmol) in CH₂Cl₂ (4 mL) was stirred at RT for 2h, then was concentrated in vacuo to give Part B compound as a whitesolid (110 mg; 95%), which was used in the next step without furtherpurification.

A solution of Part B compound (16 mg; 0.04 mmol), 2-ethyl chloroformate(5 μL, 0.06 mmol), and NaHCO₃ (15 mg; 0.2 mmol) in THF/H₂O (2 mL of a1:1 solution) was stirred at RT for 1 h. Volatiles were removed invacuo, and the residue was partitioned between EtOAc and H₂O. Theorganic phase was dried (MgSO₄) and concentrated in vacuo to give Part Ccompound, which was used in the next step without further purification.

A solution of Part C compound and LiOH.H₂O (10 mg; 0.24 mmol) in 1:1THF:H₂O (2 mL) was stirred at RT for 2 h, then was acidified to pH 2with 1 M aqueous HCl, and finally partitioned between EtOAc and H₂O. Theorganic phase was dried (MgSO₄) and concentrated in vacuo. The residuewas purified by preparative HPLC (YMC reverse-phase ODS 20×100 mmcolumn; detection at 220 nm; flow rate=20 mL/min; continuous gradientfrom 50% A to 100% B over 10 min+4 min hold time at 100% B, whereA=90:10:0.1H₂O:MeOH:TFA and B=90:10:0.1 MeOH:H₂O:TFA) and lyophilizedfrom dioxane to furnish the title compound (11 mg; 66%) as a whitesolid. [M+H]⁺=465.5

EXAMPLES 114-118

Following the procedure for the synthesis of Example 113, the followingcompounds of the invention were prepared. Example No. R [M + H]⁺ 114

479.6 115

493.6 116

513.6 117

543.6 118

493.6

EXAMPLE 119

A solution of Example 106 Part K compound (150 mg; 0.5 mmol)

α-Chloroacetonitrile (140 μL; 2.5 mmol) and K₂CO₃ (310 mg; 2.5 mmol) inCH₃CN (15 mL) was heated at 90° C. for 2 h. Solids were filtered off andthe filtrate was concentrated in vacuo. The residue was chromatographed(SiO₂; 85:15 hex:EtOAc) to give Part A compound (90 mg; 54%) as an oil.

A solution of Part A compound (90 mg; 0.2 mmol), and HCl in dioxane (0.5mL of a 4M solution; 2.0 mmol) in CH₂Cl₂ (4 mL) was stirred at RT for 3h. Volatiles were removed in vacuo to give Part B compound, which wasused in the next step without further purification.

A mixture of Part C compound, isobutyl chloroformate (37 μL; 0.3 mmol)and NaHCO₃ (80 mg; 1.0 mmol) in 1:1 THF:H₂O (4 mL) was stirred at RT for30 min, then was partitioned between EtOAc and H₂O. The organic phasewas dried (MgSO₄) and concentrated in vacuo. The residue waschromatographed (SiO₂; 3:1 hex:EtOAc) to give Part C compound (30 mg;33%) as an oil.

A solution of Part C compound (90 mg; 0.2 mmol), and 50% NH₂OH/H₂O (75mg) in MeOH (6 mL) and H₂O (3 mL) was heated at 90° C. for 3 h.Volatiles were removed in vacuo, and the residue was lyophilized fromdioxane to give Part D compound as a pink solid (75 mg), which was usedin the next step without further purification.

A solution of Part C compound (15 mg; 0.04 mmol) and4-tert-butyl-benzoyl chloride (8 μL; 0.04 mmol) in pyridine (1 mL) washeated at 115° C. for 4 h, then was cooled to RT. Volatiles were removedin vacuo, and the residue was purified by preparative HPLC (YMCreverse-phase ODS 20×100 mm column; detection at 220 nm; flow rate=20mL/min; continuous gradient from 50% A to 100% B over 10 min+5 min holdtime at 100% B, where A=90:10:0.1H₂O:MeOH:TFA and B=90:10:0.1MeOH:H₂O:TFA) to furnish Part E compound.

A solution of Part E compound and LiOH.H₂O (15 mg) in 1:1 THF:H₂O (2 mL)was stirred at RT for 4 h, then was acidified with aqueous 1 M HCl.Volatiles were removed in vacuo and the residue was purified bypreparative HPLC (YMC reverse-phase ODS 20×100 mm column; detection at220 nm; flow rate=20 mL/min; continuous gradient from 50% A to 100% Bover 10 min+5 min hold time at 100% B, where A=90:10:0.1H₂O:MeOH:TFA andB=90:10:0.1 MeOH:H₂O:TFA) and lyophilized from dioxane to furnish thetitle compound as a white lyophilate (2.0 mg; 10% yield for 2 steps).

[M+H]⁺=536.6

EXAMPLES 120-122

Following the general procedure for the synthesis of Example 119, thefollowing compounds of the invention were prepared. Example No. R [M +H]⁺ 120

524.6 121

564.5 122

556.6

EXAMPLE 123

A mixture of Example 106 Part K compound (50 mg; 0.15 mmol)

and 5-Chloromethyl-3-phenyl-[1,2,4]oxadiazole (58 mg; 0.3 mmol),

and K₂CO₃ (41 mg; 0.3 mmol) in CH₃CN (10 mL) was heated at 90° C. for 2h, then cooled to RT. Solids were filtered off, and the filtrate wasconcentrated in vacuo. The residue was chromatographed (SiO₂; 9:1 to 4:1hex:EtOAc) to give Part A compound (60 mg; 82%) as a white solid.

A solution of Part A compound (60 mg; 0.12 mmol) and HCl in dioxane (0.5mL of a 4M solution; 2.0 mmol) in CH₂Cl₂ (5 mL) was stirred at RT for 2h. The reaction was concentrated to give Part B compound as a whitesolid (45 mg; 86%), which was used in the next step without furtherpurification.

A solution of Part B compound (15 mg; 0.04 mmol), isobutyl chloroformate(7 μL, 0.06 mmol), and NaHCO₃ (12 mg; 0.16 mmol) in 1:1 THF:H₂O (2 mL)was stirred at RT for 30 min. Volatiles were removed in vacuo, and theresidue was partitioned between EtOAc and H₂O. The organic phase wasdried (MgSO₄) and concentrated in vacuo to give Part C compound, whichwas used in the next step without further purification.

A solution of crude Part C compound and LiOH.H₂O (8 mg; 0.2 mmol) in 1:1THF:H₂O (2 mL) was stirred at RT for 6 h, then was acidified to pH 2with aqueous 1 M HCl, and finally was partitioned between EtOAc and H₂O.The organic phase was dried (MgSO₄) and concentrated in vacuo. Theresidue was purified by preparative HPLC (YMC reverse-phase ODS 20×100mm column; detection at 220 nm; flow rate=20 mL/min; continuous gradientfrom 50% A to 100% B over 10 min+5 min hold time at 100% B, whereA=90:10:0.1H₂O:MeOH:TFA and B=90:10:0.1 MeOH:H₂O:TFA) and lyophilizedfrom dioxane to furnish the title compound (11 mg; 66%) as a whitesolid.

[M+H]⁺=480.0

EXAMPLES 124-125

Following the general procedure for the synthesis of Example 123, thefollowing compounds of the invention were prepared. Example No. R [M +H]⁺ 124

556.6 125

536.6

EXAMPLE 126

A solution of Example 123 Part B compound (30 mg; 0.07 mmol)

2-chloro-4-(trifluoromethyl)pyrimidine (22 μL, 0.14 mmol), and Et₃N (39μL; 0.28 mmol) in toluene (8 mL) was heated at 85° C. for 1 h. Volatileswere removed in vacuo, and the residue was chromatographed (SiO₂; 9:1 to4:1 hex:EtOAc) to give Part A compound (36 mg; 96%) as a white solid.

A solution of Part A compound (36 mg; 0.07 mmol) and LiOH.H₂O (14 mg;0.4 mmol) in 1:1 THF:H₂O (2 mL) was stirred at RT for 18 h, then wasacidified to pH 2 with aqueous 1M HCl, and finally was partitionedbetween EtOAc and H₂O. The organic phase was dried (MgSO₄) andconcentrated in vacuo. The residue was purified by preparative HPLC (YMCreverse-phase ODS 20×100 mm column; detection at 220 nm; flow rate=20mL/min; continuous gradient from 50% A to 100% B over 10 min+5 min holdtime at 100% B, where A=90:10:0.1H₂O:MeOH:TFA and B=90:10:0.1MeOH:H₂O:TFA) and lyophilized from dioxane to give the title compound asa white solid (33 mg; 94%).

[M+H]⁺=526.0

EXAMPLES 127-130

Following the general procedure for the synthesis of Example 126, thefollowing compounds of the invention were prepared (Example 129 wasprepared using Example 89 Part B compound and Example 130 was preparedusing Example 23 Part A compound). Example No. R [M + H]⁺ 127

602.6 128

582.6 129

539.5 130

553.6

EXAMPLE 131

A mixture of 3-Azido-5-hydroxy-pentan-2-one (Example 229 Part Acompound; 500 mg; 3.5 mmol)

and polymer-bound Ph₃P (1.75 g; 5.25 mmol) in dry dioxane (10 mL) wasstirred at RT for 10 min, after which benzyl-carbonyl chloride (0.9 mL;7.0 mmol) was added dropwise. The reaction was heated at 80° C. for 18h, cooled to RT and the resin was filtered off. The filtrate wasconcentrated in vacuo, and the residue was purified by preparative HPLC(YMC reverse-phase ODS 30×250 mm column; detection at 220 nm; flowrate=20 mL/min; continuous gradient from 50% A to 100% B over 30 min+7min hold time at 100% B, where A=90:10:0.1H₂O:MeOH:TFA and B=90:10:0.1MeOH:H₂O:TFA) to give Part A compound as an oil (200 mg; 17%).

A solution of Part A compound (200 mg; 0.6 mmol), and LiOH.H₂O (100 mg;2.4 mmol) in 1:1 THF:H₂O (6 mL) was heated at 50° C. for 2 h, then wascooled to RT and partitioned between EtOAc and H₂O. The organic phasewas dried (MgSO₄) and concentrated in vacuo to give crude Part Bcompound (110 mg; 85%) as an oil, which was used in the next reactionwithout further purification.

To a 0° C. solution of Part B compound (75 mg; 0.4 mmol) and Et₃N (100μL; 0.8 mmol) in CH₂Cl₂ (5 mL) was added dropwise methanesulfonylchloride (32 μL; 0.5 mmol). The reaction was warmed to RT and stirred atRT for 1.5 h, then was partitioned between CH₂Cl₂ and aqueous 1M HCl.The organic phase was washed with saturated aqueous NaHCO₃ and brine,dried (MgSO₄) and concentrated in vacuo. The residue was chromatographed(SiO₂; 9:1 to 7:3 hex:EtOAc) to give Part C compound (95 mg; 93%) as anoil.

A solution of Example 106 Part K compound (270 mg; 0.8 mmol) and HCl indioxane (1.0 mL of a 4M solution; 4.0 mmol) in CH₂Cl₂ (3 mL) was stirredat RT for 2 h. Volatiles were removed in vacuo to give crude Part Dcompound, which was used in the next step without further purification.

A solution of crude Part D compound, isobutyl chloroformate (90 μL, 0.68mmol) and NaHCO₃ (336 mg; 4.0 mmol) in THF/H₂O (6 mL of a 1:1 solution)was stirred at RT for 30 min, then was partitioned between EtOAc andH₂O. The organic phase was dried (MgSO₄) and concentrated in vacuo. Theresidue was chromatographed (SiO₂; 3:1 hex:EtOAc) to give Part Ecompound (200 mg; 74% for two steps) as an oil.

A mixture of Part C compound (30 mg; 0.1 mmol), Part D compound (15 mg;0.05 mmol), and K₂CO₃ (10 mg; 0.075 mmol) in CH₃CN (1 mL) was heated at95° C. for 30 h. Volatiles were removed in vacuo, and the residue waspartitioned between EtOAc and H₂O. The organic phase was dried (MgSO₄)and concentrated in vacuo. The residue was purified by preparative HPLC(YMC reverse-phase ODS 20×100 mm column; detection at 220 nm; flowrate=20 mL/min; continuous gradient from 50% A to 100% B over 10 min+5min hold time at 100% B, where A=90:10:0.1H₂O:MeOH:TFA and B=90:10:0.1MeOH:H₂O:TFA) to give Part F compound (13 mg; 48% yield).

A solution of Part D compound (13 mg; 0.02 mmol) and LiOH.H₂O (10 mg;0.1 mmol) in 1:1 THF:H₂O (1 mL) was stirred at RT for 18 h, then wasacidified to pH 1 with 1 M aqueous HCl and finally partitioned betweenEtOAc and H₂O. The organic phase was dried (MgSO₄) and concentrated invacuo. The residue was lyophilized from dioxane to give the titlecompound (9 mg; 39%) as a white solid. [M+H]⁺=521.6

EXAMPLES 132-143

Following the general procedure for the synthesis of Example 131, thefollowing compounds of the invention were prepared. All the appropriatearyloxazole-ethanol reagents were prepared according to the generalprocedure for the synthesis of Example 231 Part A compound. Example No.R [M + H]⁺ 132

563.7 133

537.6 134

537.6 135

542.1 136

575.6 137

575.6 138

551.6 139

542.1 140

542.1 141

537.6 142

542.1 143

537.6

EXAMPLE 144

A mixture of chiral4-(3-hydroxy-phenyl)-1-(4-trifluoromethyl-pyrimidin-2-yl)-pyrrolidine-3-carboxylicacid ethyl ester (24 mg; 0.06 mmol; obtained from chiral prep HPLCseparation of Example 243 Part A compound),

methanesulfonic acid2-[2-(4-tert-butylphenyl)-5-methyl-oxazol-4-yl]-ethyl ester (41 mg; 0.12mmol; The oxazole-ethanol was prepared according to the generalprocedure described for the synthesis of Example 231 Part A compound.The mesylate was prepared from the alcohol according to the generalprocedure described for the synthesis of Example 23 Part A compound.),

and K₂CO₃ (14 mg; 0.09 mmol) in CH₃CN (1 mL) was heated at 90° C. for 18h. More K₂CO₃ (14 mg; 0.09 mmol) was added and the heating was continuedat 90° C. for an additional 18 h. The reaction was then cooled to RT andvolatiles were removed in vacuo. The residue was taken up in MeOH (2mL), sonicated and filtered. The filtrate was concentrated in vacuo andthe residue was purified by preparative HPLC (YMC reverse-phase ODS20×100 mm column; detection at 220 nm; flow rate=20 mL/min; continuousgradient from 30% A to 100% B over 10 min+6 min hold time at 100% B,where A=90:10:0.1H₂O:MeOH:TFA and B=90:10:0.1 MeOH:H₂O:TFA) to give PartA compound (cis diastereomer; 7.6 mg; 22%).A second product isolated was Part B compound (trans diastereomer; 20mg; 57%).

A solution of Part A compound (7.6 mg; 0.01 mmol) and conc. HCl/HOAc (1mL of a 1:9 solution) was heated at 80° C. for 6 h, then was cooled toRT. Volatiles were removed in vacuo and the residue was purified bypreparative HPLC (YMC reverse-phase ODS 20×100 mm column; detection at220 nm; flow rate=20 mL/min; continuous gradient from 30% A to 100% Bover 10 min+5 min hold time at 100% B, where A=90:10:0.1H₂O:MeOH:TFA andB=90:10:0.1 MeOH:H₂O:TFA) and was lyophilized from dioxane to give thetitle compound as a white solid (2.5 mg; 34% yield). [M+H]⁺=609.6

EXAMPLE 145

Following the same procedure as for Example 144 Part C, Example 144 PartB compound was converted to the title compound. [M+H]⁺=609.6

EXAMPLES 146-147

Following the general procedure for the synthesis of Examples 144 and145, the following compounds of the invention were prepared from theenantiomer

Example No. R [M + H]⁺ 146

609.6 147

609.6

EXAMPLE 148

A solution of Example 23 Part F compound (240 mg; 0.45 mmol) in HOAc (20mL) and aqueous HCl (20% solution; 5 mL) was stirred at 85° C. for 4 h,then was cooled to RT and concentrated in vacuo to give Part A compound(200 mg; 100%) as an oil.

A mixture of part A compound (20 mg; 0.037 mmol), NaHCO₃ (8 mg; 0.09mmol) and 4-chlorophenyl chloroformate (10 μL; 0.074 mmol) in THF (0.5mL) and water (50 μL) was stirred at RT for 1 h, then concentrated invacuo. The residue was partitioned between EtOAc (2 mL) and saturatedKHSO₄ (1 mL). The organic phase was washed with brine (1 mL), dried(Na₂SO₄), and concentrated in vacuo; the residue was purified bypreparative HPLC (as described for Example 1) and lyophilized (water) togive the title compound (18.3 mg; 66%) as an oil.

[M+H]⁺=561.2

EXAMPLES 149-157

Compounds 149-157 of the invention were prepared (from Example 148 partA compound) in a similar fashion to the synthesis of Example 148 usingappropriate chloroformates.

Example # R [M + H]⁺ 149

541.3 150

507.3 151

493.3 152

507.3 153

541.3 154

557.2 155

509.3 156

521.3 157

527.2

EXAMPLES 158-163

Examples 158-163 of the invention were prepared (from Example 148 part Acompound) in a similar fashion to the synthesis of Example 148 usingappropriate acylating reagents.

Example # R Reagent [M + H]⁺ 158

517.2 159

547.2 160

506.3 161

491.1 162

505.1 163

506.1

EXAMPLE 164

A solution of Example 31 Part A compound (5 mg; 0.012 mmol),5-chloro-1-phenyl-tetrazole (15 μL; 0.11 mmol), Et₃N (40 μL; 0.29 mmol)in toluene (1 mL) was stirred at 120° C. in a sealed tube for 18 h; thenwas cooled to RT and concentrated in vacuo. The residue was partitionedbetween EtOAc (10 mL) and brine (5 mL). The organic layer was dried(Na₂SO₄) and concentrated in vacuo; the residue was purified bypreparative HPLC (as described for Example 1) and lyophilized (water) togive Part A compound (5 mg; 75%) as an oil.

A solution of Part A compound (5 mg; 0.0087 mmol) in HOAc (0.8 mL) andaqueous HCl (0.2 mL of a 20% solution) was stirred at 88° C. for 4 h;then was cooled to RT and concentrated in vacuo. The residue waspurified by preparative HPLC (as described for Example 1) andlyophilized (water) to give the title compound (2 mg; 42%) as an oil.

[M+H]⁺=551.2

¹H NMR (CD₃OD): δ 7.86 (m, 2H), 7.38 (m, 8H), 6.87 (m, 2H), 6.69 (m,2H), 4.12 (t, J=7 Hz, 2H), 3.49 (m, 1H), 3.40 (m, 1H), 3.06 (m, 1H),3.01 (m, 2H), 2.88 (t, J=7 Hz, 2H), 2.67 (m, 1H), 2.58 (m, 1H), 2.36 (m,1H), 2.28 (s, 3H)

EXAMPLES 165-169

Examples 165 through 169 of the invention were prepared in a similarfashion to the synthesis of Example 164 (from Example 31 Part Acompound) using appropriate heteroaryl chlorides.

Example # R [M + H]⁺ 165

535.2 166

568.1 167

586.1 168

499.2 169

514.2

EXAMPLE 170

A mixture of Example 23 Part E compound (1.00 g; 2.9 mmol),5-phenyl-2-methyl-oxazole-4-ethanol (700 mg; 3.4 mmol) andcyanomethylene tributylphosphorane (830 mg; 3.5 mmol) in toluene (15 mL)was stirred at 85° C. for 4 h, then was cooled to RT and concentrated invacuo. The residue was chromatographed (SiO₂; continuous gradient from7:3 to 3:7 hex:EtOA) to give Part A compound (1.30 g; 85%) as an oil.

A solution of Part A compound (1.3 g; 2.4 mmol) in DCE (10 mL) and HClin dioxane (2.5 mL of a 4M solution; 10 mmol) was stirred at RT for 3 h;then was concentrated in vacuo. The residue was partitioned betweenEtOAc (30 mL) and saturated aqueous NaHCO₃ (10 mL). The organic layerwas dried (Na₂SO₄) and concentrated in vacuo to give Part B compound(530 mg; 50%; racemate) as a colorless oil.

The individual enantiomers of racemic Part B compound (530 mg; 1.2 mmol)were separated by preparative HPLC using the following conditions:ChiralPak AD chiral column, 5 cm×50 cm, 20p; Isocratic solvent system:15:85 A:B (A=50% MeOH+50% EtOH+0.1% Et₂NH; B=100% heptane+0.1% Et₂NH);Injection volume=10 mL MeOH; Detection wavelength=220 nm; Flow rate=50mL/min. The enantiomer that eluted off the column first was Part Ccompound (245 mg; 46 mg), which was isolated as an oil. Analyticalchiral HPLC conditions: ChiralPak AD chiral column 4.6×250 mm; Isocraticsolvent system: 15% A+85% B, where Solvent A=50% MeOH+50% EtOH+0.1%Et₂NH; Solvent B=100% heptane+0.1% Et₂NH; Detection wavelength=254 nm;Flow rate=1 mL/min; Retention time=13.3 min. [α] (0.48 w/v %)_(MeOH)⁵⁸⁹=+10.9°.The other enantiomer from Part B compound (that eluted off the columnlater than Part C compound) was identified as Part D compound (245 mg;46%), which was isolated as an oil. Under the identical chiralanalytical HPLC conditions as for Part C compound, the retention time ofPart D compound=26.7 min. [α](0.50 w/v %)_(MeOH) ⁵⁸⁹=−12.3°.

A solution of Part C compound (225 mg; 0.52 mmol),2-chloro-4-trifluoromethylpyrimidine (77 μL; 0.64 mmol), Et₃N (130 μL;0.93 mmol) in toluene (4.5 mL) was stirred at 60° C. in a sealed tubefor 3 h; then was cooled to RT and concentrated in vacuo. The residuewas partitioned between EtOAc (10 mL) and brine (5 mL). The organiclayer was dried (Na₂SO₄) and concentrated in vacuo; the residue waschromatographed (SiO₂; continuous gradient from 100% hex to 1:1hex:EtOAc) to provide Part E compound (300 mg; 100%) as a colorless oil.

A solution of Part E compound (300 mg; 0.52 mmol) in HOAc (4 mL) andaqueous HCl (1 mL of a 20% solution) was stirred at 70° C. for 18 h;then was cooled to RT and concentrated in vacuo. The residue waspartitioned between EtOAc (30 mL) and water (10 mL). The organic layerwas washed with brine (10 mL), dried (Na₂SO₄) and concentrated in vacuo;the residue was purified by preparative HPLC (as described forExample 1) and lyophilized (dioxane) to give the title compound (230 mg;81%) as a white solid.

[M+H]⁺=553.2

[α](0.96w/v %)_(MeOH) ⁵⁸⁹=−70.8°

Analytical chiral HPLC: Chiralpak AD chiral column 4.6×250 mm, 10μ;Isocratic solvent system: 3:7 A:B, where Solvent A=100% IPA+0.1% TFA;Solvent B=100% heptane

Detection=254 nm; Flow rate=2 mL/min;

Retention time=6.7 min.

¹H NMR (CD₃OD): δ 8.41 (m, 1H), 7.85 (m, 2H), 7.36 (m, 3H), 7.00 (d, J=9Hz, 2H), 6.76 (m, 3H), 4.13 (m, 2H), 3.81 (m, 1H), 3.62 (m, 1H), 3.51(m, 2H), 3.18 (m, 1H), 2.87 (m, 2H), 2.73 (m, 2H), 2.41 (m, 1H), 2.28(s, 3H)Alternative Synthesis of Example 170 Part C Compound:

Crude Example 184 Part G compound was purified by HPLC (YMCreverse-phase ODS 20×100 mm column; flow rate=20 mL/min; 10 mincontinuous gradient from 20:100 B:A to 100% B+2 min hold-time at 100% B,where solvent A=90:10:0.1H₂O:MeOH:TFA and solvent B=90:10:0.1MeOH:H₂O:TFA) to give pure Example 184 Part G compound as a whitelyophilate. To a solution of the lyophilate in EtOH (10 mL) was addedHCl in dioxane (3 mL of a 1 N solution), and the reaction was stirredfor 24 h at RT, then was concentrated in vacuo. The residue was purifiedby HPLC (YMC reverse-phase ODS 20×100 mm column; flow rate=20 mL/min; 10min continuous gradient from 25:100 B:A to 100% B+2 min hold-time at100% B, where solvent A=90:10:0.1H₂O:MeOH:TFA and solvent B=90:10:0.1MeOH:H₂O:TFA) to give material which was identical in every respect topure Example 170 Part C compound (13 mg; 33%). [α]_(Methanol) ⁵⁸⁹=+14.27° (c=XX mg/mL)

EXAMPLE 171

Part A compound (300 mg; 100%) was prepared from Example 170 Part Dcompound (225 mg; 0.52 mmol) using the same procedure as described forthe synthesis of Example 170 Part E compound.

The title compound was prepared from Part A compound (225 mg; 0.52 mmol)using the procedure employed in the synthesis of Example 170 Part Fcompound. The title compound was obtained (180 mg; 63%) as a white solidafter preparative HPLC (using the same conditions as described inExample 1)

[M+H]⁺=553.2

[α] (0.96w/v %)_(MeOH) ⁵⁸⁹=+70.4°

Analytical chiral HPLC: Chiralpak AD chiral column; 4.6×250 mm, 10μ;Isocratic solvent system: 30% A+70% B, where Solvent A=100% IPA+0.1%TFA; Solvent B=100% heptane

Detection=254 nm; Flow rate=2 mL/min

Retention time=10.1 min.

¹H NMR (CD₃OD): δ 8.41 (m, 1H), 7.85 (m, 2H), 7.36 (m, 3H), 7.00 (d, J=9Hz, 2H), 6.76 (m, 3H), 4.13 (m, 2H), 3.81 (m, 1H), 3.62 (m, 1H), 3.51(m, 2H), 3.18 (m, 1H), 2.87 (m, 2H), 2.73 (m, 2H), 2.41 (m, 1H), 2.28(s, 3H)

EXAMPLE 172

The title compound was prepared from the reaction of Example 170 Part Ccompound (131 mg; 0.30 mmol) with isobutyl chloroformate (50 μL; 0.45mmol) using the same 2-step sequence as employed in the synthesis ofExample 148 from Example 170 Part C compound. The title compound wasobtained (75 mg; 44%) as a white solid after preparative HPLC (using thesame conditions as described in Example 1)

[M+H]⁺=507.2

¹H NMR (CD₃OD): δ 7.86 (m, 2H), 7.37 (m, 3H), 6.99 (m, 2H), 7.75 (m,2H), 4.13 (m, 2H), 3.72 (m, 2H), 3.58 (m, 1H), 3.41 (m, 1H), 3.21 (m,3H), 3.03 (m, 1H), 2.87 (m, 2H), 2.71 (m, 1H), 2.59 (m, 1H), 2.33 (m,1H), 1.80 (s, 3H), 0.81 (q, J=7 Hz, 6H)

EXAMPLE 173

The title compound was prepared from the reaction of Example 170 Part Ccompound (109 mg; 0.25 mmol) with phenyl chloroformate (50 μL; 0.45mmol) using the same 2-step sequence as employed in the synthesis ofExample 148 from Example 170 Part C compound. The title compound wasobtained (80 mg; 61%) as a white solid after preparative HPLC (using thesame conditions as described for the purification of Example 1 compound)

[M+H]⁺=527.2

¹H NMR (CD₃OD): δ 7.85 (m, 2H), 7.37 (m, 3H), 7.26 (m, 2H), 7.10 (m,1H), 7.00 (m, 4H), 6.78 (m, 2H), 4.13 (m, 2H), 3.80 (m, 1H), 3.65 (m,1H), 3.45 (m, 1H), 3.24 (m, 1H), 3.11 (m, 1H), 2.87 (m, 2H), 2.74 (m,1H), 2.66 (m, 1H), 2.42 (m, 1H), 2.27 (d, J=5 HZ, 3H)

EXAMPLE 174

To a −40° C. suspension of 2-chloropyrimidine (2.8 mL; 24.6 mmol) inEt₂O (75 mL) was added a solution of methyl lithium in Et₂O (20 mL of a1.4 M solution; 28 mmol). The mixture was stirred at −40° C. for 30 min,then was allowed to warm to 0° C. and stirred at 0° C. for 30 min. Aftercooling to −40° C., a solution of HOAc (1.7 mL), water (0.3 mL) and THF(10 mL) was added dropwise, followed by a solution of DDQ (7.0 g in 25mL THF). The mixture was allowed to warm to RT and was stirred at RT for10 min, then cooled to 0° C. Aqueous NaOH (1.2 g in 10 mL of H₂O) wasadded, and the mixture was stirred at 0° C. for 10 min. The organicphase was dried (MgSO₄/K₂CO₃) and concentrated in vacuo to give Part Acompound (1.1 g; 35%) as a solid.

The title compound was prepared from the reaction of Example 170 Part Ccompound (100 mg; 0.24 mmol) with Part A compound (34 mg; 0.26 mmol)using the same 2-step sequence as employed in the synthesis of Example170 from Example 170 Part C compound. The title compound was obtained(90 mg; 78%) as a white solid after preparative HPLC (using the sameconditions as described in Example 1).

[M+H]⁺=499.2

Analytical chiral HPLC: Chiral AD column; 4.6×250 mm, 10μ; Isocraticsolvent system: 20% A+80% B; Solvent A=100% IPA+0.1% TFA; Solvent B=100%heptane+0.1% TFA; Detection=261 nm; Flow rate=1 mL/min; Retentiontime=10.86 min.

¹H NMR (CD₃OD): δ 8.13 (m, 1H), 7.94 (m, 2H), 7.46 (m, 3H), 7.14 (m,2H), 6.86 (m, 3H), 4.22 (t, J=6 Hz, 2H), 4.12 (m, 1H), 3.83 (m, 1H),3.57 (m, 1H), 3.42 (m, 1H), 3.32 (m, 1H), 2.97 (m, 4H), 2.55 (m, 4H),2.39 (s, 3H)

EXAMPLE 175

The title compound was prepared from Example 170 Part D compound (60 mg;0.14 mmol) with Example 174 Part A compound (23 mg; 0.18 mmol) using the2-step sequence as employed in the synthesis of Example 170 from Example170 Part D compound. The title compound was obtained (50 mg; 73%) as awhite solid after preparative HPLC (using the same conditions asdescribed in Example 1)

[M+H]⁺=499.2

Chiral Analytical HPLC: Chiralpak AD chiral column; 4.6×250 mm, 10μ;Isocratic solvent system: 20% A+80% B; Solvent A=100% IPA+0.1% TFA;Solvent B=100% heptane+0.1% TFA; Detection=261 nm; Flow rate=1 mL/min

Retention time=17.32 min.

¹H NMR (CD₃OD): δ 8.17 (m, 1H), 7.94 (m, 2H), 7.45 (m, 3H), 7.13 (m,2H), 6.85 (m, 3H), 4.20 (t, J=6 Hz, 2H), 4.11 (m, 1H), 3.83 (m, 1H),3.57 (m, 1H), 3.42 (m, 1H), 3.32 (m, 1H), 2.97 (m, 4H), 2.55 (m, 4H),2.39 (s, 3H)

EXAMPLE 176

A solution of Example 31 Part A compound (600 mg; 1.38 mmol) anddiketene (126 μL; 1.7 mmol) in MeCN (4 mL) was stirred at 70° C. for 4h, then was cooled to RT and concentrated in vacuo. The residue waschromatographed (SiO₂; continuous gradient from 100% EtOAc to 1:4MeOH/EtOAc) to give Part A compound (450 mg; 63%) as an oil.

A solution of Part A compound (15 mg; 0.029 mmol) in HOAc (0.8 mL) andaqueous HCl (0.2 mL of a 20% solution) was stirred at 70° C. for 18 h;then was cooled to RT and concentrated in vacuo. The residue waspurified by preparative HPLC (as described for Example 1) andlyophilized (water) to give the title compound (8 mg; 56%) as an oil.

[M+H]⁺=491.2

¹H NMR (CD₃OD): δ 7.86 (m, 2H), 7.37 (m, 3H), 7.00 (m, 2H), 6.76 (m,2H), 4.13 (t, J=6 Hz, 2H), 3.67 (m, 1H), 3.59 (m, 1H), 3.26 (m, 2H),3.20 (m, 2H), 3.15 (m, 1H), 3.05 (m, 1H), 2.87 (m, 2H), 2.70 (m, 1H),2.37 (m, 1H), 2.28 (s, 3H), 2.10 (m, 3H)

EXAMPLE 177

To a solution of Example 176 Part A compound (100 mg; 0.19 mmol) andphenylhydrazine (19 μL; 0.19 mmol) in EtOH (1 mL), was addedmethanesulfonic acid (6 μL). The mixture was stirred at RT for 3 h; thenpyridine (100 μL) was added and the mixture was concentrated in vacuo.The residue was dissolved in pyridine (1 mL) and POCl₃ (54 μL; 0.58mmol) was added. The mixture was stirred at RT for 18 h, after which thereaction was quenched by adding water (0.2 mL). The mixture waspartitioned between EtOAc (10 mL) and saturated aqueous NaHCO₃ (5 mL).The organic layer was dried (Na₂SO₄) and concentrated in vacuo; theresidue was purified by preparative HPLC (as described for Example 1)and lyophilized (water) to give the title compound (18 mg; 17%) as anoil.

Example 177 title compound (3.4 mg; 71%) was prepared from Part Acompound (5 mg; 0.008 mmol) using the same procedure as described inExample 164 title compound.

[M+H]⁺=563.3

¹H NMR (CD₃OD): δ 7.95 (m, 2H), 7.53 (m, 5H), 7.46 (m, 4H), 7.94 (m,2H), 6.78 (m, 2H), 4.20 (t, J=6 Hz, 2H), 3.42 (m, 1H), 3.36 (m, 1H),3.24 (m, 1H), 2.97 (m, 5H), 2.76 (m, 1H), 2.67 (m, 1H), 2.39 (s, 3H),2.32 (s, 3H)

EXAMPLE 178

A solution of Example 170 Part E compound (30 mg; 0.052 mmol) andLiOH.H₂O (15 mg; 0.35 mmol) in THF (0.8 mL), MeOH (0.3 mL) and H₂O (0.3mL) was stirred at RT for 2.5 h, then was concentrated in vacuo. Theresidue was partitioned between aqueous HCl (5 mL of a 1N solution) andEtOAc (20 mL). The organic phase was washed with brine (5 mL), dried(Na₂SO₄) and concentrated in vacuo; the residue was purified bypreparative HPLC (as described for Example 1) and lyophilized (dioxane)to give the title compound (3 mg; 11%) as a white solid.

[M+H]⁺=553.3

¹H NMR (CD₃OD): δ 8.41 (m, 1H), 7.85 (m, 2H), 7.37 (m, 3H), 7.05 (d, J=8Hz, 2H), 6.77 (d, J=8 Hz, 2H), 6.69 (s, 1H), 4.14 (m, 2H), 3.81 (m, 1H),3.71 (m, 2H) 2.94 (m, 2H), 2.85 (m, 4H), 2.62 (m, 1H), 2.27 (m, 3H)

EXAMPLE 179

A solution of Example 171 Part A compound (50 mg; 0.087 mmol) andLiOH.H₂O (15 mg; 0.35 mmol) in THF (1 mL), MeOH (0.2 mL) and H₂O (0.2mL) was stirred at RT for 3 h, then was concentrated in vacuo. Theresidue was partitioned between aqueous HCl (5 mL of a 1N solution) andEtOAc (20 ml). The organic phase was washed with brine (5 mL), dried(Na₂SO₄) and concentrated in vacuo; the residue was purified bypreparative HPLC (as described for Example 1) and lyophilized (dioxane)to give the title compound (10 mg; 21%) as a white solid.

[M+H]⁺=553.3

¹H NMR (CDCl₃): δ 8.40 (m, 1H), 7.92 (m, 2H), 7.26 (m, 3H), 7.02 (d, J=8Hz, 2H), 6.75 (d, J=8 Hz, 2H), 6.69 (d, J=5 Hz, 1H), 4.14 (m, 2H), 3.90(m, 1H), 3.71 (m, 2H), 2.94 (m, 2H), 2.85 (m, 4H), 2.62 (m, 1H), 2.31(m, 3H)

EXAMPLE 180

Part A compound was synthesized in a similar fashion as Example 31 PartA compound from Example 23 Part F compound from the corresponding methylester (which was synthesized exactly according to the sequence used forthe synthesis of Example 23 Part F compound except that methylpropynoate was used in the synthesis of the methyl ester of Example 23Part B compound).

A solution of Part A compound (50 mg; 0.12 mmol) andtrimethylsilylisocyanate (20 μL; 0.14 mmol) in THF (1 mL) was stirred atRT for 18 h. Volatiles were removed in vacuo and the residue waspartitioned between EtOAc (10 mL) and brine (5 mL). The organic layerwas dried (Na₂SO₄) and concentrated in vacuo to give Part B compound (60mg; 100%) as an oil.

A solution of Part B compound (60 mg; 0.13 mmol) andbromotrifluoroacetone (17 μL; mmol) in toluene (1.5 mL) was stirred at80° C. for 3 h. Volatiles were removed in vacuo and the residue waschromatographed (SiO₂; continuous gradient from 85:15 to 2:3 hex:EtOAc)to provide compound (25 mg; 35%) as a colorless oil.

A solution of Part C compound (8 mg; 0.014 mmol) and LiOH.H₂O (4 mg;0.092 mmol) in THF (0.33 mL), MeOH (0.15 mL) and H₂O (0.15 mL) wasstirred at RT for 1 h, then was concentrated in vacuo. The residue waspartitioned between aqueous HCl (5 mL) and EtOAc (20 mL). The organicphase was dried (Na₂SO₄) and concentrated in vacuo; the residue waspurified by preparative HPLC (as described for Example 1) andlyophilized (dioxane) to give the title compound (2.1 mg; 27%) as asolid.

[M+H]⁺=542.3

¹H NMR (CD₃OD): δ 7.95 (m, 2H), 7.84 (m, 1H), 7.46 (m, 3H), 7.12 (d, J=8Hz, 2H), 6.86 (d, J=8 Hz, 2H), 4.22 (t, J=4 Hz, 2H), 3.83 (m, 1H), 3.69(m, 1H), 3.45 (m, 1H), 3.38 (m, 1H), 3.24 (m, 1H), 2.96 (t, J=8 Hz, 2H),2.84 (m, 2H), 2.49 (m, 1H), 2.37 (m, 3H)

In addition, a second, slower eluting fraction from the preparative HPLCof the crude hydrolysis product mixture was identified as the epimerizedtrans-isomer Example 181 (2.0 mg; 26%):

EXAMPLE 181

[M+H]⁺=542.3

¹H NMR (CD₃OD): δ 7.95 (m, 2H), 7.84 (m, 1H), 7.46 (m, 3H), 7.12 (d, J=8Hz, 2H), 6.86 (d, J=8 Hz, 2H), 4.22 (t, J=4 Hz, 2H), 3.81 (m, 1H), 3.72(m, 1H), 3.54 (m, 1H), 3.30 (m, 1H), 2.97 (m, 3H), 2.90 (m, 1H), 2.80(m, 1H), 2.63 (m, 1H), 2.37 (m, 3H)

EXAMPLE 182

solution of Example 180 Part C compound (15 mg; 0.03 mmol) in HOAc (0.8mL) and aqueous HCl (0.2 mL of a 20% solution) was stirred at 70° C. for3 days. The mixture was concentrated in vacuo and the residue waspurified by preparative HPLC (as described for Example 1) andlyophilized (water) to give the title compound (13 mg; 86%) as an oil.

[M+H]⁺=559.2

EXAMPLE 183

The title compound (5 mg; 9.6%) was prepared employing the sameprocedure as described in Example 164 Part B compound from Example 170Part C compound (50 mg; 0.12 mmol).

[M+H]⁺=449.4

¹H NMR (CD₃OD): δ 8.01 (m, 2H), 7.53 (m, 3H), 7.15 (t, J=9 Hz, 2H), 6.91(m, 2H), 4.27 (t, J=4 Hz, 2H), 3.84 (m, 1H), 3.74 (m, 1H), 3.65 (m, 1H),3.49 (m, 1H), 3.29 (m, 1H), 3.17 (m, 1H), 3.03 (m, 2H), 2.73 (m, 1H),2.51 (m, 1H), 2.45 (m, 3H), 2.03 (m, 3H)

EXAMPLE 184

Part A compound (186 mg; 100%) was prepared from Example 170 Part Ccompound (200 mg; 0.46 mmol) using the procedure described in Example148 Part A compound.

The title compound was prepared from the reaction of Part A compound (15mg; 0.035 mmol) with benzyl chloroformate (15 μL; 0.14 mmol) using theprocedure as employed in the synthesis of Example 148. The titlecompound was obtained (10 mg; 54%) as an oil after preparative HPLC(using the same conditions as described in Example 1)

[M+H]⁺=541.3

¹H NMR (CD₃OD): δ 7.95 (m, 2H), 7.48 (m, 3H), 7.33 (m, 5H), 7.05 (m,2H), 6.83 (m 2H), 5.10 (m, 2H), 4.22 (t, J=4 Hz, 2H), 3.71 (m, 1H), 3.52(m, 1H), 3.30 (m, 2H), 3.12 (m, 1H), 2.96 (m, 2H), 2.78 (m, 1H), 2.69(m, 1H), 2.42 (m, 1H), 2.37 (m, 3H)

[α] (0.97 w/v %)_(MeOH) ⁵⁸⁹ =−33.7°An alternative synthesis of Example 184 compound is shown using thefollowing sequence:

To a 0° C. solution of (R)-(+)-(1-phenylethyl)maleimide (3 g; 15 mmol)

and Example 1 Part B compound (4.56 g; 19.2 mmol) in CH₂Cl₂ (50 mL) wasadded TFA (0.1 mL). The solution was allowed to warm to RT and stirredat RT for 2 h, then was concentrated in vacuo. The residue waschromatographed (SiO₂; 4:1 hex:EtOAc) to give Part C compound (4.2 g;84%) as a white solid.

To a −20° C. (CCl₄/dry ice bath) solution of Part C Compound (1.5 g; 4.4mmol) in THF (5 mL) was 4-tert-butyldimethylsilyloxyphenyl magnesiumbromide in THF (15 mL of a 0.58 M solution) over 1 h using a syringepump. The reaction was complete by HPLC 30 min after the addition hadbeen completed, after which EtOH (30 mL) was added followed by NaBH₄(0.42 g; 11 mmol). The mixture was stirred for 2 h at 0° C. and for 18 hat RT. The mixture was concentrated in vacuo and the residue waspartitioned between EtOAc and aqueous 10% K₂CO₃. The organic layer wasdried (MgSO₄) and concentrated in vacuo. The residue was dissolved intoluene (50 mL) and the mixture was stirred at 110° C. for 8 h, then wascooled to RT and concentrated in vacuo. The residue was chromatographed(SiO₂; 9:1 hex:EtOAc) to give Part D compound as a clear oil (0.92 g;45%).

To a 0° C. solution of Part D compound (500 mg; 1.18 mmol) in THF (5 mL)was added (n-Bu)₄NF (1.3 mL of a 1 M solution in THF; 1.0 mmol). Themixture was stirred at 0° C. for 30 min, then was concentrated in vacuoto give crude Part E compound (360 mg; 99%) as an oil.

A mixture of crude Part E compound (360 mg; 1.2 mmol) in MeCN (10 mL),Example 23 Part A compound (400 mg; 1.42 mmol) and K₂CO₃ (196 mg; 1.42mmol) was stirred at 85° C. for 18 h, then was cooled to RT andconcentrated in vacuo. The residue was partitioned between EtOAc (20 mL)and brine (10 mL). The organic layer was separated, dried (Na₂SO₄) andconcentrated in vacuo; the residue was chromatographed (SiO₂; gradientfrom 100% hex to 3:7 hex:EtOAc) to give Part F compound (320 mg; 55%) asa colorless oil.

A mixture of Part F compound (600 mg; 1.2 mmol) and 10% Pd/C (30 mg) inHOAc (24 mL) was stirred under an atmosphere of H₂ (60 psi) for 18 h.The mixture was filtered through Celite®; the Celite® pad was washedwith MeOH (30 mL). The combined filtrates were concentrated in vacuo togive Part G compound (500 mg; 100%) as an oil. This material wasconfirmed to be the 3S, 4R enantiomer by conversion to Example 170 PartC compound (see Example 170).

The title compound (130 mg; 75%) was prepared from the reaction of PartG compound (130 mg; 0.32 mmol) with benzyl chloroformate (46 μL; 0.32mmol) using the same procedure as described for the synthesis of Example148 Part B compound.

EXAMPLE 185

The title compound was prepared from Example 184 Part A compound (15 mg;0.035 mmol) with p-tolyl chloroformate (10 μL; 0.09 mmol) using theprocedure as employed in the synthesis of Example 148. The titlecompound (10 mg; 54%) was obtained as an oil after preparative HPLC(using the same conditions as described in Example 1).

[M+H]⁺=541.3

¹H NMR (CD₃OD): δ 7.95 (m, 2H), 7.47 (m, 3H), 7.13 (m, 4H), 6.95 (m,2H), 6.86 (m 2H), 4.22 (t, J=4 Hz, 2H), 3.86 (m, 1H), 3.74 (m, 1H), 3.52(m, 1H), 3.33 (m, 1H), 3.20 (m, 1H), 2.98 (m, 2H), 2.84 (m, 1H), 2.75(m, 1H), 2.49 (m, 1H), 2.36 (m, 3H), 2.31 (s, 3H)

[α] (0.69 w/v %)_(MeOH) ⁵⁸⁹=−50.6°

Example 185 (135 mg; 78%) was also prepared from Example 184 Part Ecompound (130 mg; 0.32 mmol) with p-tolyl chloroformate (50 μL; 0.35mmol) using the same procedure as described for the synthesis of Example148 Part B compound.

EXAMPLE 186

The title compound (5 mg; 20%) was prepared from Example 180 Part Acompound (20 mg; 0.048 mmol) with 2,6-dichloropyrazine (15 mg; 0.10mmol) using the same procedure as described for the synthesis of Example164.

[M+H]⁺=519.2

EXAMPLE 187

The title compound (6 mg; 18%) was prepared from Example 148 Part Acompound (25 mg; 0.062 mmol) with 2,4-dichloro-6-methylpyrimidine (15mg; 0.092 mmol) using the procedure described in Example 164 Part Acompound.

[M+H]⁺=533.1

¹H NMR (CD₃OD): δ 7.95 (m, 2H), 7.46 (m, 3H), 7.12 (m, 2H), 6.87 (d, J=4Hz, 2H), 6.50 (m, 1H), 4.21 (m, 2H), 4.07 (m, 1H), 3.83 (m, 1H), 3.70(m, 1H), 3.62 (m, 1H), 3.51 (m, 1H), 3.37 (m, 1H), 2.97 (m, 2H), 2.90(m, 1H), 2.50 (m, 1H), 2.37 (s, 3H), 2.34 (m, 3H)

A second compound (later fraction), identified as Example 188 (3 mg; 9%)was also obtained from the preparative HPLC purification.

[M+H]⁺=533.1

¹H NMR (CD₃OD): δ 7.95 (m, 2H), 7.46 (m, 3H), 7.12 (m, 2H), 6.87 (d, J=4Hz, 2H), 6.67 (m, 1H), 4.24 (m, 2H), 3.97 (m, 1H), 3.74 (m, 1H), 3.54(m, 1H), 3.43 (m, 1H), 3.30 (m, 2H), 2.97 (m, 2H), 2.86 (m, 1H), 2.50(m, 1H), 2.38 (m, 6H)

EXAMPLE 188 EXAMPLE 189

The title compound (5 mg; 18%) was prepared from Example 148 Part Acompound (20 mg; 0.050 mmol) with 2,4-dichloropyrimidine (15 mg; 0.10mmol) using the same procedure as described for the synthesis of Example164 Part A compound.

[M+H]⁺=519.2

A second compound (later fraction, identified as Example 190 (2 mg; 8%)was also obtained from the preparative HPLC purification.

[M+H]⁺=519.1

EXAMPLE 190 EXAMPLE 191

Part A compound was synthesized from (R)-(+)-(1-phenylethyl)maleimideemploying the identical synthetic sequence used for the synthesis ofExample 184 Part D compound except that 4-tetrahydropyranyloxy-phenylmagnesium bromide was used instead of4-tert-butyldimethylsilyloxy-phenyl magnesium bromide.

A solution of Part A compound (200 mg; 0.51 mmol) in CH₂Cl₂ (5 mL) at RTand p-toluenesulfonic acid.H₂O (116 mg; 0.61 mmol) was stirred at RT for4 h; then was concentrated in vacuo to give crude Part B compound (150mg; 96%).

Part C compound (30 mg; 58%) was prepared by the reaction of crude PartB compound (30 mg; 0.097 mmol) with the mesylate Example 277 Part Ecompound (33 mg; 0.11 mmol) using the procedure described in Example 184Part F compound.

Part D compound (20 mg; 100%) was prepared from Part C compound (30 mg;0.057 mmol) using the procedure described for the preparation of Example184 Part G compound.

The title compound (20 mg; 65%) was prepared from Part D compound (20mg; 0.057 mmol) and isobutyl chloroformate (8 μL; 0.057 mmol) using thesame procedure as described for the synthesis of Example 148 compound.

[M+H]⁺=537.4

¹H NMR (CD₃OD): δ 7.51 (m, 2H), 7.37 (m, 1H), 7.07 (d, J=8 Hz, 2H), 7.01(d, J=8 Hz, 1H), 6.84 (d, J=8 Hz, 2H), 4.21 (m, 2H), 3.84 (s, 3H), 3.81(m, 2H), 3.67 (m, 1H), 3.50 (m, 1H), 3.29 (m, 2H), 3.12 (m, 1H), 2.95(m, 2H), 2.79 (m, 1H), 2.68 (m, 1H), 2.42 (m, 1H), 2.36 (s, 3H), 1.89(m, 1H), 0.89 (dd, J=6 Hz, 6H)

EXAMPLE 192

Part A compound (30 mg; 58%) was prepared by the reaction of Example 191Part B compound (30 mg; 0.097 mmol) with the mesylate Example 264 Part Bcompound (33 mg; 0.11 mmol) using the procedure described for thepreparation of Example 184 Part F compound.

Part B compound (20 mg; 100%) was prepared from Part A compound (30 mg;0.057 mmol) using the procedure described in Example 184 Part Gcompound.

Part C compound (15 mg; 49%) was prepared from Part B compound (20 mg;0.057 mmol) with isobutyl chloroformate (8 μL; 0.057 mmol) using theprocedure described for the synthesis of Example 148.

[M+H]⁺=537.3

EXAMPLE 193

Part A compound (the 3R,4S enantiomer; 200 mg; 25%) was isolated fromracemic Example 23 Part F compound (800 mg; 1.50 mmol) by preparativeHPLC using the following conditions: ChiralPak AD column, 5 cm×50 cm,20p; Isocratic solvent system: 10% A:90% B (A=100% IPA+0.1% HOAc; B=100%hex+0.1% HOAc); Injection volume=10 mL in IPA; Detection=220 nm; Flowrate=50 mL/min. Analytical chiral HPLC: Chiralpak AD column 4.6×250 mmIsocratic solvent system: 10% A+90% B; Solvent A=100% IPA+0.1% HOAc;Solvent B=100% hex+0.1% HOAc; Detection=254 nm; Flow rate=1 mL/min

Retention time=5.7 min.

A solution of Part A compound (5 mg; 0.0094 mmol) in HOAc (1 mL) andaqueous HCl (0.25 mL of a 20% solution) was stirred at 85° C. for 18 h.Volatiles were removed in vacuo, and the residue was dissolved in THF (1mL). Saturated aqueous NaHCO₃ (0.5 mL) and di-tert-butyl dicarbonate (10mg; 0.046 mmol) were added. The reaction was stirred at RT for 3 h, thenwas quenched by the addition of saturated aqueous NH₄CL (0.5 mL). Themixture was partitioned between EtOAc (50 mL) and saturated aqueousNH₄CL (10 mL). The organic phase was dried (Na₂SO₄) and concentrated invacuo. The residue was purified by preparative HPLC (as described forExample 1) and lyophilized (water) to give the title compound (3 mg;63%) as a white solid.

[M+H]⁺=506.6

Part B compound was also prepared from Example 170 Part C compound usingthe following synthetic route:

A solution of Example 170 Part C compound (350 mg; 0.81 mmol) in HOAc (4mL) and aqueous HCl (1 mL of a 20% solution) was stirred at 85° C. for 6h. Volatiles were removed in vacuo and the residue was dissolved in THF(5 mL); the pH was adjusted to ˜9 with saturated aqueous NaHCO₃, afterwhich (Boc)₂O (280 mg; 1.28 mmol) was added. The reaction was stirred atRT for 18 h, then was quenched with saturated aqueous NH₄Cl solution (50mL) to adjust the pH to ˜3-4. The organic phase was dried (Na₂SO₄), andconcentrated in vacuo. The residue was chromatographed (SiO₂; continuousgradient from 100% hex to 100% EtOAc) to give a yellow oil, which waslyophilized from dioxane to give the title compound (250 mg; 61%) as alight yellow solid.

[M+H]⁺=506.6

[α] (12 mg/2 mL)_(MeOH) ⁵⁸⁹=−33.67°

EXAMPLE 194

The title compound (150 mg; 61%) was prepared from Example 170 Part Dcompound (210 mg; 0.48 mmol) using the same procedure as described inthe second synthetic route for the preparation of Example 193 compound.

[M+H]⁺=506.6

[α] (8.8 mg/2 mL)_(MeOH) ⁵⁸⁹=+33.93

EXAMPLE 195

The title compound (34 mg; 51%) was prepared from Example 180 Part Acompound (50 mg; 0.12 mmol) and 2-chloro-5-bromopyrimidine (100 mg)using the 2-step procedure employed in the synthesis of Example 164.

[M+H]⁺=563.2

EXAMPLE 196

The title compound (31 mg; 51%) was prepared from Example 180 Part Acompound (50 mg; 0.12 mmol) with 2-chloro-5-ethylpyrimidin (100 mg)using the same 2-step procedure as employed in the synthesis of Example164.

[M+H]⁺=513.3

EXAMPLE 197

To a mixture of Example 32 Part F compound (1.66 g; 4.9 mmol) and2-(5-methyl-2-phenyl-oxazol-4-yl)-ethanol (1.11 g, 5.4 mmol) in toluene(40 mL) was added cyanomethylenetributylphosphine (3.58 g; 14.8 mmol)dropwise. The mixture was heated at 80° C. for 3 h, cooled to RT,concentrated in vacuo and partitioned between EtOAc and water. Theorganic phase was washed with water (2×) and brine, dried (Na₂SO₄) andconcentrated in vacuo. The residue was chromatographed (SiO₂; stepwisegradient from hexane to hex:EtOAc 2:3) to give Part A compound (2.44 g;95%) as an oil.

A solution of Part A compound (2.34 g; 4.49 mmol) and 4M HCl in dioxane(50 mL) in CH₂Cl₂ (50 ml) was stirred at RT for 4.5 h, then concentratedin vacuo and partitioned between EtOAc and saturated aqueous NaHCO₃. Theorganic layer was washed with saturated aqueous NaHCO₃ (2×), water andbrine, dried (Na₂SO₄) and concentrated in vacuo to give Part B compound(1.72 g; 91%) as an orange oil.

The individual enantiomers of Part B compound were separated bypreparative HPLC using a CHIRALCEL OD column from Chiral TechnologiesInc (5 cm ID×50 cm, 20μ): flow rate=45 mL/min; isocraticconditions=80:20 A:B, where A=heptane+0.1% Et₂NH; B=iPrOH+0.1% Et₂NH;detector wavelength=279 nm. The first fraction from the chiralpreparative HPLC was identified as the desired 3R,4S enantiomer (760 mg;Part C compound). Chiral analytical HPLC using a Daicel Chiralcel OD4.6×500 mm column: flow rate=1 mL/min; isocratic conditions=80:20 A:B,where A=heptane+0.1% Et₂NH; B=IPA+0.1% Et₂NH; detector wavelength=279nm; retention time=21 min. Optical rotation=+13.36°The second (slower-eluting) fraction (660 mg) from the chiral prep HPLCseparation was identified as the opposite enantiomer (Part D compound).Chiral analytical HPLC (same conditions as above) retention time=29 min.Optical rotation=−13.60°

To a 0° C. solution of Part C 3R,4S enantiomer (10.0 mg; 0.0238 mmol)and aqueous saturated NaHCO₃ (0.50 mL) in THF (0.50 mL) was added4-chlorophenyl chloroformate (4.0 μL; 0.0286 mmol). The reaction wasstirred at 0° C. for 30 min, then was allowed to warm to RT and stirredovernight at RT. Volatiles were removed in vacuo, and the residue waspartitioned between EtOAc and water. The aqueous layer was extractedwith EtOAc (2×). The combined organic extracts were washed with water(1×) and brine (1×), dried (Na₂SO₄) and concentrated in vacuo to givePart E compound, which was used in the next reaction without furtherpurification.

A solution of Part E compound in HOAc (0.80 mL) and concentrated HCl(0.20 mL) was shaken at 70° C. for 6.5 h, then cooled to RT andconcentrated in vacuo. The residue was purified by preparative HPLC (YMCCombiprep ODS-A 30×50 mm column; flow rate=35 mL/min; 8 min continuousgradient from 20:80 B:A to 100% B, where solvent A=90:10:0.1H₂O:MeOH:TFAand solvent B=90:10:0.1 MeOH:H₂O:TFA) to give the title compound (6.3mg; 47%).

[M+H]⁺=561.23

EXAMPLES 198-219

Examples 198 through 219 were prepared in a similar fashion to Example197 (from Example 197 Part C compound) using appropriate chloroformates.

Example # R [M + H]⁺ 198

541.3 199

507.33 200

491.28 201

493.3 202

507.33 203

586.27 204

541.3 205

605.21 206

545.27 207

557.28 208

585.27 209

509.31 210

493.29 211

489.26 212

521.34 213

575.25 214

497.27 215

557.28 216

561.22 217

569.21 218

513.22 219

465.29

EXAMPLE 220

The racemic Example 21 Part C compound (970 mg) was purified by chiralpreparative HPLC using the same conditions as described in Example 197Part C. The desired 3R,4S enantiomer shown above was obtained (140 mg;chiral analytical HPLC retention time=16 min).

A solution of chiral Part A compound (10 mg; 0.0230 mmol) in HOAC (800μL) and concentrated HCl (200 μL) was shaken at 70° C. overnight.Concentration of the reaction solution in vacuo yielded the pure titlecompound (10.1 mg; 94%).

[M+H]⁺=407.44

EXAMPLE 221

To a 0° C. solution of Example 220 (6.1 mg; 0.015 mmol) in saturatedaqueous NaHCO₃ (0.50 mL) and THF (0.50 mL) was added di-tert-butyldicarbonate (4 mg; 0.017 mmol). The reaction was stirred at 0° C. for 10min, then was allowed to warm to RT and stirred at RT for 2.5 h.Volatiles were removed in vacuo; water and EtOAc were added. The mixturewas cooled to 0° C. and the aqueous phase was acidified to pH 1 withsaturated aqueous KHSO₄ and extracted with EtOAc (2×). The combinedorganic extracts were washed with water (2×) and brine, dried (Na₂SO₄)and concentrated in vacuo. The residue was purified by preparative HPLC(as described for Example 197 Part F) to yield the title compound (3.2mg, 42%).

[M+H]⁺=507.30

EXAMPLE 222

To a solution of Example 220 (9.3 mg; 0.023 mmol) in THF (250 μL) andsaturated aqueous NaHCO₃ (250 μL) was added ethyl isocyanate (2.18 μL;0.0276 mmol) at RT. The reaction was stirred at RT overnight. More ethylisocyanate (2.2 μL) was added to drive the reaction to completion (6 h),after which volatiles were removed in vacuo. The residue was dissolvedin water, cooled to 0° C. and acidified to pH 1 with saturated aqueousKHSO₄. A white precipitate formed. The aqueous phase was extracted withEtOAc (3×). The combined organic extracts were washed with water (2×)and brine, dried (Na₂SO₄), filtered and concentrated in vacuo. Theresidue was purified by preparative HPLC (Phenomenex Luna 5μ 21.2×100 mmcolumn; flow rate=20 mL/min; 10 min continuous gradient from 20:80 B:Ato 100% B, where solvent A=90:10:0.1H₂O:MeOH:TFA and solvent B=90:10:0.1MeOH:H₂O:TFA) to give the title compound (9.6 mg; 87%).

[M+H]⁺=478.49

EXAMPLE 223

To a solution of Example 220 (9.3 mg; 0.023 mmol) in THF (250 μL) andsaturated aqueous NaHCO₃ (250 μL) was added phenyl isocyanate (3.75 μL;0.0345 mmol) at RT. The reaction was stirred at room temperatureovernight and then concentrated down. The solid residue was redissolvedinto water, cooled in an ice bath, and acidified to pH 1.0 withsaturated aqueous KHSO₄. This acidic solution was extracted with EtOAc(3×). The combined extracts were washed with water (2×) and brine, driedover anhydrous sodium sulfate, filtered and concentrated. The productwas purified by preparative HPLC (as described for Example 222) to yieldthe title compound (9.1 mg; 75%).

[M+H]⁺=526.49

EXAMPLE 224

To a solution of Example 220 Part A compound (10 mg; 0.0230 mmol) inCH₂Cl₂ (500 μL) was added TEA (4.8 μL; 0.035 mmol) and phenylacetylchloride (3.7 μL; 0.028 mmol). The reaction was stirred at RT for 3 h,then was concentrated in vacuo. The residue was partitioned betweenEtOAc and water; the organic phase was washed with water (2×) and brine,dried (Na₂SO₄) and concentrated in vacuo to give Part A compound (12.5mg) as a yellow oil, which was used in the next step without furtherpurification.

A solution of Part A compound in HOAc (800 μL) and concentrated HCl (200μL). The reaction was shaken at 70° C. for 13.5 h, then cooled to RT andconcentrated in vacuo. The residue was purified by preparative HPLC (asdescribed for Example 222) to yield the title compound (5.0 mg; 41%) asa solid.

[M+H]⁺=525.50.

EXAMPLE 225

Example 225 (7.1 mg; 65%) was synthesized employing the proceduredescribed in Example 224, except that butyryl chloride was used in thesequence instead of phenylacetyl chloride. [M+H]⁺=477.50.

EXAMPLE 226

A solution of Example 220 (9.3 mg; 0.023 mmol) and phenylsulfonylchloride (4.4 μL; 0.035 mmol) in THF (250 μL) and saturated aqueousNaHCO₃ (250 μL) was stirred at RT for 3.5 h, then was concentrated invacuo. The residue was taken up in water, cooled to 0° C., and acidifiedto pH 1 with saturated aqueous KHSO₄ (precipitate formation). Themixture was extracted with EtOAc (3×). The combined organic extractswere washed with water (2×) and brine, dried (Na₂SO₄) and concentratedin vacuo. The residue was purified by preparative HPLC (as described forExample 222) to yield the title compound (8.1 mg; 64%). [M+H]⁺=547.46

EXAMPLE 227

Example 227 (4.4 mg; 38%) was synthesized employing the proceduredescribed in Example 226, except that ethane sulfonyl chloride was usedin the sequence instead of phenyl sulfonyl chloride. [M+H]⁺=499.46

EXAMPLE 228

To a RT solution of Example 220 (9.3 mg; 0.023 mmol) in THF (250 μL) andsaturated aqueous NaHCO₃ (250 μL) was added N-methyl-N-phenylcarbamoylchloride (4.7 mg; 0.028 mmol). The reaction was stirred at RT for 3.5 h,then was concentrated in vacuo. The residue was dissolved into water,cooled to 0° C., and acidified to pH 1.0 with saturated aqueous KHSO₄(precipitate formation). The mixture was extracted with EtOAc (3×). Thecombined organic extracts were washed with water (2×) and brine, dried(Na₂SO₄) and concentrated in vacuo. The product was purified bypreparative HPLC (as described for Example 222) to yield the titlecompound (6.5 mg; 52%) as a solid.

[M+H]⁺=540.24

EXAMPLE 229

A mixture of 3-chloro-5-hydroxy-2-pentanone (5 g; 36.7 mmol) and sodiumazide (4.8 g; 73.8 mmol) in acetone (100 mL) and H₂O (˜30 mL) wasstirred at 50° C. for 2.5 h. The reaction was cooled to RT and theacetone was removed in vacuo. The aqueous phase was extracted withCH₂Cl₂; the combined organic extracts were dried (Na₂SO₄) andconcentrated in vacuo. The residue was chromatographed (SiO₂; continuousgradient from 100% hex to 100% EtOAc) to give Part A compound (4.38 g;82%).

A mixture of Part A compound (500 mg; 3.50 mmol) and resin-bound Ph₃P(1.50 g of 3 mmol/g resin; 4.50 mmol) in dioxane (20 mL) was shaken for10 min at RT.

Phenylacetyl chloride (1 g; 6.50 mmol) was added and the reaction washeated at 80° C. for 18 h, then cooled to RT and filtered. A mixture ofthe filtrate in MeOH (20 mL) and aqueous LiOH (6 mL of a 2N solution)was shaken at 70° C. for 15 min. and more aqueous LiOH 2N was addeduntil the pH of the solution remained at 9. The mixture was concentratedin vacuo and partitioned between water and CH₂Cl₂; the aqueous layer wasextracted with CH₂Cl₂. The combined organic extracts were dried (Na₂SO₄)and concentrated in vacuo. The residue was chromatographed (SiO₂;continuous gradient from 20% hex/EtOAc to 100% EtOAc) to give Part Bcompound (140 mg; 19%) as a pale yellow oil.

[M+H]⁺=218; ¹H NMR (CDCl₃) δ 7.31 (m, 5H), 4.03 (s, 2H), 3.87 (t, J=6.0Hz, 2H), 2.64 (t, J=6.0 Hz, 2H 2.19 (s, 3H).

A mixture of Example 23 Part D compound (4.8 g; 10 mmol) and 10% Pd/C(500 mg) in HOAc (100 mL) was stirred under an atmosphere of H₂ (60 psi)for 18 h. The catalyst was filtered off on Celite® and the filtrate wasconcentrated in vacuo. The residue was azeotroped with toluene, then wastreated with 1N HCl in dioxane (50 mL) for 10 min. and concentrated invacuo to afford Part C compound (3.3 g; 95%) as an orange oil which wasused in the next step without further purification.

[M+H]⁺=250.11

To a mixture of part C compound (300 mg, 1.05 mmol) in THF (3 mL) andsaturated aqueous Na₂CO₃ (5 mL) was added ethyl chloroformate (120 μL,1.30 mmol), and the reaction was stirred overnight at RT. The THF wasremoved in vacuo and the aqueous solution was extracted with CH₂Cl₂; thecombined organic extracts were dried (Na₂SO₄) and concentrated in vacuo.The residue was chromatographed (SiO₂; continuous gradient from 100% hexto 100% EtOAc) to give Part D compound (110 mg; 32%). [M+H]⁺=322.18

A mixture of Part D compound (13 mg, 40 μmol), part B compound (10.3 mg,48 μmol), cyanomethylene tributylphosphine (30 μL, 120 μmol) in toluene(0.5 mL) was heated at 70° C. for 18 h. The mixture was concentrated invacuo and the resulting residue was chromatographed (SiO₂; continuousgradient from 100% hex to 60% EtOAc) to give part E compound as an oil.([M+H]+=521.24)

A solution of Part E compound in 25% concentrated HCl in HOAc (1 mL) washeated at 70° C. for 8 h. Volatiles were removed in vacuo and theresidue was purified by HPLC (as described for Example 1) andlyophilized (water with 2-4% methanol) to give the title compound (5.0mg; 26% over 2 steps) as a white solid.

[M+H]⁺=493.20

EXAMPLE 230

To a mixture of Example 229 part C compound (300 mg, 1.05 mmol), THF (3mL) and saturated aqueous Na₂CO₃ (5 mL) was added phenyl chloroformate(160 μL, 1.30 mmol). The reaction was stirred overnight at RT, afterwhich the THF was removed in vacuo and the resulting aqueous solutionwas extracted with CH₂Cl₂. The combined organic extracts were dried(Na₂SO₄) and concentrated in vacuo. The residue was chromatographed(SiO₂; continuous gradient from 100% hex to 100% EtOAc) to give Part Acompound (140 mg; 36%) as a colorless oil.

[M+H]⁺=370.14

A mixture of Part A compound (15 mg, 40 μmol), Example 229 part Bcompound (10.3 mg, 48 μmol), cyanomethylene tributylphosphine (30 μL,120 μmol) in toluene (0.5 mL) was heated at 70° C. for 18 h. Volatileswere removed in vacuo and the residue was chromatographed (SiO₂;continuous gradient from 100% hexane to 60:4 hex:EtOAc) to give Part Bcompound as an oil.

[M+H]+=569.18

A solution of Part B compound in 25% concentrated HCl in HOAc (1 mL) washeated at 70° C. for 20 h. The mixture was concentrated in vacuo and theresidue was purified by preparative HPLC (as described for Example 1)and lyophilized (water with 2-4% methanol) to give the title compound(10.5 mg; 48% over 2 steps) as a white solid.

[M+H]⁺=541.18

EXAMPLE 231

A mixture of example 229 part A compound (500 mg; 3.50 mmol) andresin-bound Ph₃P (1.50 g of 3 mmol/g resin; 4.50 mmol) in dioxane (20mL) was shaken for 10 min at RT. 3-chlorobenzoyl chloride (1.22 g; 6.50mmol) was then added and the reaction was heated at 80° C. for 18 h,then cooled to RT, filtered and concentrated in vacuo. The residue wasdissolved in MeOH (10 mL) and THF (10 mL) and aqueous LiOH (6 mL of a 2Nsolution) was added. The mixture was shaken at 50° C. and more aqueousLiOH was added until the pH of the solution remained constant at 9. Themixture was then heated at 50° C. for 6 h, cooled to RT andconcentrated. The residue was partitioned between H₂O and CH₂Cl₂; thecombined organic extracts were dried (Na₂SO₄) and concentrated in vacuo.The residue was chromatographed (SiO₂; continuous gradient from 20%hex/EtOAc to 100% EtOAc) to give Part A compound (80 mg; 9%).

[M+H]⁺=260.36;

A mixture of Example 230 part A compound (15 mg, 40 μmol), part Acompound (11.4 mg, 48 μmol) and cyanomethylene tributylphosphine (30 μL,120 μmol) in toluene (0.5 mL) was heated at 70° C. for 18 h. The mixturewas concentrated in vacuo and the resulting residue was chromatographed(SiO₂; continuous gradient from 100% hex to 60:40 EtOAc) to give Part Bcompound.

[M+H]⁺=589.44

A solution of Part B compound in concentrated HCl/HOAc (1 mL of a 1:3mixture) was heated at 70° C. for 18 h. The mixture was concentrated invacuo and the residue was purified by preparative HPLC (as described forExample 1) and lyophilized (water with 2-4% methanol) to give the titlecompound (5.6 mg; 25% for 2 steps) as a white solid.

[M+H]⁺=561.63

EXAMPLE 232

A mixture of example 229 part D compound (13 mg, 40 μmol), example 231part A compound (11.4 mg, 48 μmol) and cyanomethylene tributylphosphine(30 μL, 120 μmol) in toluene (0.5 mL) was heated at 70° C. for 18 h. Themixture was concentrated in vacuo and the resulting residue waschromatographed (SiO₂; continuous gradient from 100% hex to 60% EtOAc)to give the ethyl ester of part E compound ([M+H]⁺=541.46). This esterwas dissolved in 25% concentrated HCl in acetic acid (1 mL) and heatedat 70° C. for 18 h. The mixture was concentrated and the residue waspurified by HPLC (as described for Example 1) and lyophilized (waterwith 2-4% methanol) to give the title compound (3.5 mg; 18%) as a whitesolid.

[M+H]⁺=513.54

EXAMPLE 233

Part A compound was synthesized according to the general proceduredescribed for the synthesis of Example 231 Part A compound except that4-tert-butylbenzoyl chloride was used instead of 3-chlorobenzoylchloride.

The title compound (11 mg; 50%) was prepared from Part A compound andExample 230 part A compound (15 mg; 40 μmol) using the same sequence asfor Example 231 except that 4-tert-butylbenzoyl chloride (1.37 g; 6.50mmol) was used instead of 3-chlorobenzoyl chloride.

[M+H]+=583.64

EXAMPLE 234

The title compound (7 mg; 30%) was prepared from example 229 part Dcompound (13 mg, 40 μM),using the same sequence as for Example 232except that 4-tert-butylbenzoyl chloride (1.37 g; 6.50 mmol) was usedinstead of 3-chlorobenzoyl chloride.

[M+H]⁺=535.64

EXAMPLES 235-241

Examples 235-241 of the invention were prepared in a similar fashion toExample 43 (from Example 43 Part D compound) using a variety ofchloroformates.

Example # R [M + H]⁺ 235

491.1 236

491.1 237

505.1 238

505.1 239

539.0 240

525.0 241

555.0

EXAMPLE 242

A mixture of Example 43, part C compound (105 mg; 0.202 mmol) and 10%Pd/C (75 mg) in MeOH/HOAc (3 mL of a 1:1 solution) was stirred at RTunder an atmosphere of H₂ (75 psi) for 48 h. The catalyst was filteredoff on Celite® and the filtrate was concentrated in vacuo to give Part Acompound (85 mg; 81%).

[M+H]⁺=521.5

A mixture of Part A compound (10 mg; 0.019 mmol) and LiOH.H₂O (8 mg;0.19 mmol) in THF/H₂O (1 mL of a 1:1 solution) was stirred at RT for 16h, after which the pH was adjusted to ˜5 with aqueous 1 M HCl. Themixture was extracted with EtOAc (2 mL). The organic phase wasconcentrated in vacuo and the residue was purified by preparative HPLC(YMC reverse-phase ODS 20×100 mm column; flow rate=20 mL/min; 10 mincontinuous gradient from 30:70 B:A to 100% B+5 min hold-time at 100% B,where solvent A=90:10:0.1H₂O:MeOH:TFA and solvent B=90:10:0.1MeOH:H₂O:TFA). The product was further chromatographed (SiO₂, EtOAc) togive the title compound (2.3 mg; 24%) as a colourless oil.

[M+H]⁺=507.1

EXAMPLE 243

A mixture of Example 229 Part C compound (920 mg; 3.69 mmol)

and 2-chloro-4-(trifluoromethyl)pyrimidine (0.53 mL; 4.43 mmol) and Et₃N(1.03 mL; 7.38 mmol) in toluene (12.3 mL) was stirred at 80° C. for 2 h,after which the reaction was partitioned between EtOAc (65 mL) andaqueous 1 M HCl (25 mL). The organic phase was washed with H₂O (2×65 mL)and brine (70 mL), dried (MgSO₄) and concentrated in vacuo. The residuewas chromatographed (SiO₂; continuous gradient from 90% hex to 100%EtOAc) to give Part A compound (918 mg; 63%) as a colorless oil.

A mixture of 4-chloromethyl-5-methyl-2-phenyloxazole (12.6 mg; 0.0608mmol),

Part A compound (12 mg; 0.0304 mmol) and K₂CO₃ (8.4 mg; 0.0608 mmol) inCH₃CN (1 mL) was stirred at 70° C. for 15 h, after which the reactionwas partitioned between EtOAc (10 mL) and H₂O (5 mL). The organic phasewas washed with brine (20 mL), dried (MgSO₄) and concentrated in vacuoto provide crude Part B compound as an oil, which was used in the nextstep without further purification.

A solution of Part B compound LiOH.H₂O (5.1 mg) in THF (1 mL) and H₂O(0.5 mL) was stirred at RT for 16 h and then heated to 70° C. for anadditional 6 h, after which the reaction mixture was cooled to RT andthe pH was adjusted to ˜2 with aqueous 1 N HCl. The mixture waspartitioned between EtOAc (10 mL) and H₂O (5 mL). The organic phase waswashed with brine (20 mL), dried (MgSO₄) and concentrated in vacuo; theresidue was purified by preparative HPLC (as described for Example 1except that a continuous gradient from 30:70 Solvent A:Solvent B to 100%B over 10 min was used, followed by 4 min hold at 100% B) to give twocompounds. The compound with the shorter retention time on HPLC waslyophilized from 1,4-dioxane to give the title compound (1.8 mg; 11% fortwo steps) as a white solid.

[M+H]⁺=539.0

The second compound (longer retention time) was determined to be thecorresponding epimerized trans-isomer of Example 243. This compound wasalso lyophilized from 1,4-dioxane to give Example 244 (1.1 mg; 6.7% for2 steps) as a white solid.

EXAMPLE 244

[M+H]⁺=539.0

EXAMPLE 245

A mixture of Example 25 Part C compound (11.8 mg; 0.0608 mmol), Example243 Part A compound (12 mg; 0.0304 mmol) and K₂CO₃ (8.4 mg; 0.0608 mmol)in CH₃CN (1 mL) was stirred at 70° C. for 15 h, then was cooled to RTand partitioned between EtOAc (10 mL) and H₂O (5 mL). The organic phasewas washed with brine (20 mL), dried (MgSO₄) and concentrated in vacuoto provide crude Part A compound as an oil, which was used in the nextstep without further purification.

A solution of crude Part A compound in HOAc/concentrated HCl (1.2 mL ofa 9:1 solution) was stirred at 70° C. for 17 h, then was cooled to RTand concentrated in vacuo. The residue was purified by preparative HPLC(as described for Example 1 except that a continuous gradient from 30:70Solvent A:Solvent B to 100% B over 10 min was used, followed by 4 minhold at 100% B) to give the title compound (2.0 mg; 13% for 2 steps) asa white solid.

[M+H]⁺=526.0

EXAMPLE 246

A mixture of Example 23 Part E compound (640 mg; 1.83 mmol),α-chloroacetonitrile (0.232 mL; 3.66 mmol) and K₂CO₃ (506 mg; 3.66 mmol)in CH₃CN (9.2 mL) at 70° C. was stirred for 18 h, then was cooled to RTand partitioned between EtOAc (150 mL) and H₂O (80 mL). The organicphase was washed with brine (20 mL), dried (MgSO₄) and concentrated invacuo. The residue was chromatographed (SiO₂; continuous gradient from100% hex to 100% EtOAc over 55 min) to give Part A compound (590 mg;83%) as an oil.

A solution of Part A compound (590 mg; 1.52 mmol) and HCl (0.76 mL of a4 M solution in dioxane) in CH₂Cl₂ (4 mL) was stirred at RT for 3 h,then was concentrated in vacuo to give crude Part B compound (355 mg;81%) as an oil.

A mixture of Part B compound (355 mg; 1.23 mmol) and2-chloro-4-(trifluoromethyl)pyrimidine (0.298 mL; 2.47 mmol) and Et₃N(0.344 mL; 2.47 mmol) in toluene (5 mL) was stirred at 80° C. for 2 h,after which the reaction was partitioned between EtOAc (35 mL) andaqueous 1 M HCl (15 mL). The organic phase was washed with H₂O (2×35 mL)and brine (40 mL), dried (MgSO₄) and concentrated in vacuo. The residuewas chromatographed (SiO₂; continuous gradient from 90% hex to 100%EtOAc) to give Part C compound (246 mg; 46%) as a colorless oil.

A mixture of Part C compound (246 mg; 0.567 mmol) and hydroxylamine (112mg of a 50% solution in water; 1.70 mmol) in MeOH:H₂O (6 mL of a 2:1solution) was heated to reflux for 5 h, after which volatiles wereremoved in vacuo. The residue was partitioned between EtOAc (30 mL) andH₂O (15 mL). The organic phase was washed with brine (40 mL), dried(MgSO₄) and concentrated in vacuo to provide crude Part D compound (208mg, 79%) as an oil.

A mixture of Part D compound (30 mg; 0.0642 mmol), piperonyloyl chloride(23.6 mg; 0.128 mmol) in toluene (1 mL) was shaken at 115° C. for 6 h,then was cooled to RT and concentrated in vacuo. The residue waspurified by preparative HPLC (as described for Example 1 except that acontinuous gradient from 30:70 Solvent A:Solvent B to 100% B over 10 minwas used, followed by 4 min hold at 100% B) to give the title compound(14 mg, 37%) as an oil.

A solution of Part E compound (14 mg; 0.0235 mmol) in HOAc/concentratedHCl (1.5 mL of a 9:1 solution) was stirred at 70° C. for 17 h, then wascooled to RT and concentrated in vacuo. The residue was purified bypreparative HPLC (as described for Example 1 except that a continuousgradient from 30:70 Solvent A:Solvent B to 100% B over 10 min was used,followed by 4 min hold at 100% B) to give the title compound (6.4 mg;48%) as a white solid.

[M+H]⁺=570.0

EXAMPLES 247-250

Example 247 through 250 were prepared in a similar fashion to Example246 (from Example 246 part D compound) using a variety of acidchlorides.

Example # R [M + H]⁺ 247

582.0 248

602.1 249

609.9 250

570.4

A mixture of 4-tert-butyl-benzonitrile (5.0 g; 31.4 mmol), hydroxylaminehydrochloride (3.27 g; 47.1 mmol) and K₂CO₃ (8.68 g; 62.8 mmol) in EtOH(170 mL) was stirred at reflux for 18 h, then was cooled to RT andfiltered. The filtrate was concentrated in vacuo to provide crude Part Acompound as a solid, which was used in the next step without furtherpurification

To a solution of crude Part A compound in CH₂Cl₂ (50 mL) at RT was addedα-chloroacetyl chloride (2.97 mL; 37.3 mmol) followed by Et₃N (5.2 mL;37.3 mmol). The reaction mixture was stirred at RT for 2 h, after whichvolatiles were removed in vacuo and the residue was dissolved in toluene(80 mL). The reaction mixture was then heated at reflux for 12 h, thenwas cooled to RT and partitioned between EtOAc (150 mL) and H₂O (100mL). The organic phase was washed with brine (200 mL), dried (MgSO₄) andconcentrated in vacuo. The residue was chromatographed (SiO₂; continuousgradient from 100% hex to 100% EtOAc) to give Part B compound (746 mg;9.5% for 2 steps) as a solid.

A mixture of Part B compound (25.5 mg; 0.102 mmol), Example 243 Part Acompound (20 mg; 0.051 mmol) and K₂CO₃ (14.1 mg; 0.102 mmol) in CH₃CN(1.2 mL) was stirred at 90° C. for 14 h, after which the reaction waspartitioned between EtOAc (10 mL) and H₂O (5 mL). The organic phase waswashed with brine (20 mL), dried (MgSO₄) and concentrated in vacuo toprovide crude Part B compound as an oil, which was used in the next stepwithout further purification.

A solution of Part C compound in HOAc/concentrated HCl (1.2 mL of a 9:1solution) was stirred at 70° C. for 17 h, then was cooled to RT andconcentrated in vacuo. The residue was purified by preparative HPLC (asdescribed for Example 1 except that a continuous gradient from 30:70Solvent A:Solvent B to 100% B over 10 min was used, followed by 4 minhold at 100% B) to give the title compound (10.4 mg; 35%) as a whitesolid.

[M+H]⁺=582.0

EXAMPLE 252

A mixture of 4-biphenylcarbonitrile (5.0 g; 27.9 mmol), hydroxylaminehydrochloride (2.9 g; 41.8 mmol) and K₂CO₃ (7.7 g; 55.8 mmol) in EtOH(150 mL) was stirred at reflux for 18 h, then was cooled to RT andfiltered. The filtrate was concentrated in vacuo to provide crude Part Acompound as a solid, which was used in the next step without furtherpurification

To a solution of crude Part A compound in CH₂Cl₂ (50 mL) at RT was addedα-chloroacetyl chloride (2.7 mL; 33.5 mmol) followed by Et₃N (4.7 mL;33.5 mmol). The reaction mixture was stirred at RT for 2 h, after whichvolatiles were removed in vacuo and the residue was dissolved in toluene(80 mL). The reaction mixture was then heated and stirred at reflux for13 h, after which the mixture was cooled to RT. The reaction was thenpartitioned between EtOAc (150 mL) and H₂O (100 mL). The organic phasewas washed with brine (200 mL), dried (MgSO₄) and concentrated in vacuo.The residue was chromatographed (SiO₂; continuous gradient from 100% hexto 100% EtOAc) to give Part B compound (431 mg; 5.7% for 2 steps) as asolid.

A mixture of Part B compound (27.5 mg; 0.102 mmol), Example 243 Part Acompound (20 mg; 0.051 mmol) and K₂CO₃ (14.1 mg; 0.102 mmol) in CH₃CN(1.2 mL) was stirred at 90° C. for 14 h, then was cooled to RT andpartitioned between EtOAc (10 mL) and H₂O (5 mL). The organic phase waswashed with brine (20 mL), dried (MgSO₄) and concentrated in vacuo toprovide crude Part B compound as an oil, which was used in the next stepwithout further purification.

A solution of Part C compound in HOAc/concentrated HCl (1.2 mL of a 9:1solution) was stirred at 70° C. for 17 h, then was cooled to RT andconcentrated in vacuo. The residue was purified by preparative HPLC (asdescribed for Example 1 except that a continuous gradient from 30:70Solvent A:Solvent B to 100% B over 10 min was used, followed by 4 minhold at 100% B) to give the title compound (4.1 mg; 13%) as a whitesolid.

[M+H]⁺=602.0

EXAMPLE 253

A solution of Example 51 Part B compound (329 mg; 0.82 mmol) and HCl(0.41 mL of a 4 M solution in dioxane; 1.64 mmol) in CH₂Cl₂ (5 mL) wasstirred at RT for 3 h, then was concentrated in vacuo to give crude PartA compound (188 mg; 76%) as an oil.

A mixture of crude Part A compound (188 mg; 0.623 mmol) and2-chloro-4-(trifluoromethyl)pyrimidine (0.150 mL; 1.25 mmol) and Et₃N(0.175 mL; 1.25 mmol) in toluene (6.2 mL) was stirred at 80° C. for 2 h,then was cooled to RT and partitioned between EtOAc (35 mL) and aqueous1 M HCl (15 mL). The organic phase was washed with H₂O (2×35 mL) andbrine (40 mL), dried (MgSO₄) and concentrated in vacuo. The residue waschromatographed (SiO₂; continuous gradient from 90% hex to 100% EtOAc)to give Part B compound (170 mg; 61%) as a colorless oil.

A mixture of Part B compound (170 mg; 0.379 mmol) and hydroxylamine (75mg of a 50% solution in water; 1.138 mmol) in MeOH:H₂O (5 mL of a 2:1solution) was heated at reflux for 5 h, then was cooled to RT andconcentrated in vacuo. The residue was partitioned between EtOAc (30 mL)and H₂O (15 mL). The organic phase was washed with brine (40 mL), dried(MgSO₄) and concentrated in vacuo to provide crude Part C compound (149mg, 82%) as an oil.

A mixture of Part C compound (28 mg; 0.0582 mmol), 4-tert-butylbenzoylchloride (22.8 mg; 0.116 mmol) in toluene (1 mL) was shaken at 115° C.for 6 h, then was cooled to RT and concentrated in vacuo. The residuewas purified by preparative HPLC (as described for Example 1 except thata continuous gradient from 30:70 Solvent A:Solvent B to 100% B over 10min was used, followed by 4 min hold at 100% B) to give Part D compound(22 mg, 61%) as an oil.

A solution of Part D compound (22 mg; 0.0353 mmol) in HOAc/concentratedHCl (1.3 mL of a 9:1 solution) was stirred at 70° C. for 16 h, then wascooled to RT and concentrated in vacuo. The residue was purified bypreparative HPLC (as described for Example 1 except that a continuousgradient from 30:70 Solvent A:Solvent B to 100% B over 10 min was used,followed by 4 min hold at 100% B) to give the title compound (10.8 mg;51%) as a white solid.

[M+H]⁺=596.5

EXAMPLES 254-255

Examples 254-255 of the invention were prepared in a similar fashion toExample 253 (from Example 253 part C compound) using a variety of acidchlorides.

Example # R [M + H]⁺ 254

570.1 255

574.1

EXAMPLE 256

A mixture of 4-chloromethyl-5-phenylisoxazole (14.7 mg; 0.076 mmol),Example 243 Part A compound (15 mg; 0.038 mmol) and K₂CO₃ (10.5 mg;0.076 mmol) in CH₃CN (1 mL) was heated at 90° C. for 16 h, after whichthe reaction was partitioned between EtOAc (10 mL) and H₂O (5 mL). Theorganic phase was washed with brine (20 mL), dried (MgSO₄) andconcentrated in vacuo to provide crude Part A compound as an oil, whichwas used in the next step without further purification.

A solution of Part A compound and LiOH.H₂O (8.0 mg; 0.19 mmol) in THF(1.2 mL) and H₂O (0.6 mL) was stirred at 60° C. for 12 h, then wascooled to RT and the pH was adjusted to ˜2 with aqueous 1 N HCl. Themixture was partitioned between EtOAc (10 mL) and H₂O (5 mL). Theorganic phase was washed with brine (20 mL), dried (MgSO₄) andconcentrated in vacuo. The residue was purified by preparative HPLC (asdescribed for Example 1 except that a continuous gradient from 30:70Solvent A:Solvent B to 100% B over 10 min was used, followed by 4 minhold at 100% B) to give two compounds. The compound with the shorterretention time was lyophilized from 1,4-dioxane to give the titlecompound (8.1 mg; 41% for 2 steps) as a white solid.

[M+H]⁺=525.3

The second compound (longer retention time) was determined to be thecorresponding epimerized trans-isomer of Example 256. This compound wasalso lyophilized from 1,4-dioxane to give Example 257 (1.1 mg; 5.5% forsteps) as a white solid.

EXAMPLE 257

[M+H]⁺=525.3

EXAMPLE 258

A mixture of 5-chloromethyl-3-phenylisoxazole (14.7 mg; 0.076 mmol),Example 243 Part A compound (15 mg; 0.038 mmol) and K₂CO₃ (10.5 mg;0.076 mmol) in CH₃CN (1 mL) was heated at 90° C. for 16 h, then wascooled to RT and partitioned between EtOAc (10 mL) and H₂O (5 mL). Theorganic phase was washed with brine (20 mL), dried (MgSO₄) andconcentrated in vacuo to provide crude Part A compound as an oil, whichwas used in the next step without further purification.

A solution of crude Part A compound and LiOH.H₂O (8.0 mg; 0.19 mmol) inTHF (1.2 mL) and H₂O (0.6 mL) was stirred at 60° C. for 12 h, then wascooled to RT and the pH was adjusted to ˜2 with aqueous 1 N HCl. Themixture was partitioned between EtOAc (10 mL) and H₂O (5 mL). Theorganic phase was washed with brine (20 mL), dried (MgSO₄) andconcentrated in vacuo. The residue was purified by preparative HPLC (asdescribed for Example 1 except that a continuous gradient from 30:70Solvent A:Solvent B to 100% B over 10 min was used, followed by 4 minhold at 100% B) to give two compounds. The compound with the shorterretention time was lyophilized from 1,4-dioxane to give the titlecompound (4.0 mg; 20% for 2 steps) as a white solid.

[M+H]⁺=525.3

The second compound (longer retention time) was determined to be thecorresponding epimerized trans-isomer of Example 258. This compound wasalso lyophilized from 1,4-dioxane to give Example 259 (1.0 mg; 5.0% for2 steps) as a white solid.

EXAMPLE 259

[M+H]⁺=525.3

EXAMPLE 260

To a solution of Example 243 Part A compound (16 mg; 0.0405 mmol) intoluene (0.4 mL) were successively added Example 233 Part A compound(15.7 mg; 0.0608 mmol) and cyanomethylene tri-n-butylphosphorane (29.4mg; 0.122 mmol). The reaction mixture was heated to 80° C. for 8 h, thenwas cooled to RT and concentrated in vacuo. The residue was purified bypreparative HPLC (as described for Example 1 except that a continuousgradient from 30:70 Solvent A:Solvent B to 100% B over 10 min was used,followed by 4 min hold at 100% B) to give Part A compound (7.3 mg; 28%).

A solution of Part A compound (7.3 mg; 0.011 mmol) and LiOH.H₂O (8.5 mg;0.202 mmol) in THF (1.2 mL) and H₂O (0.6 mL) was stirred at 60° C. for15 h, then was cooled to RT and the pH was adjusted to ˜2 with aqueous 1N HCl. The mixture was partitioned between EtOAc (10 mL) and H₂O (5 mL).The organic phase was washed with brine (20 mL), dried (MgSO₄) andconcentrated in vacuo. The residue was purified by preparative HPLC (asdescribed for Example 1 except that a continuous gradient from 30:70Solvent A:Solvent B to 100% B over 10 min was used, followed by 4 minhold at 100% B) to give two compounds. The compound with the shorterretention time was lyophilized from 1,4-dioxane to give the titlecompound (2.6 mg; 39%) as a white solid.

[M+H]⁺=609.5

The second compound (longer retention time) was determined to be thecorresponding epimerized trans-isomer of Example 260. This compound wasalso lyophilized from 1,4-dioxane to give Example 261 (1.2 mg; 4.9% fortwo steps) as a white solid.

EXAMPLE 261

[M+H]⁺=609.4

EXAMPLE 262

The title compound (4.8 mg; 21%) was prepared from Example 229 Part Bcompound (13.2 mg; 0.0608 mmol) and Example 243 Part A compoundaccording to the procedure described for the synthesis of Example 261.

[M+H]⁺=567.4

EXAMPLE 263

The title compound (1.2 mg; 5.2%) was obtained from Example 229 Part Bcompound (13.2 mg; 0.0608 mmol) and according to the general proceduredescribed for the synthesis of Example 262.

[M+H]⁺=567.4

EXAMPLE 264

Part A compound was synthesized according to the general proceduredescribed for the synthesis of Example 231 Part A compound except that4-methoxybenzoyl chloride was used instead of 3-chlorobenzoyl chloride.

Part B compound was synthesized from Part A compound according to thegeneral procedure described for the synthesis of Example 23 Part Acompound.

A mixture of Example 243 Part A compound (20 mg; 0.051 mmol), Part Bcompound (24 mg; 0.076 mmol) and K₂CO₃ (21 mg; 0.152 mmol) in CH₃CN (1.0mL) was stirred at 90° C. for 22 h, then was cooled to RT andpartitioned between EtOAc (10 mL) and H₂O (5 mL). The organic phase waswashed with brine (20 mL), dried (MgSO₄) and concentrated in vacuo. Theresidue was purified by preparative HPLC (as described for Example 1except that a continuous gradient from 30:70 Solvent A:Solvent B to 100%B over 10 min was used, followed by 4 min hold at 100% B) to give Part Ccompound (14.5 mg; 47%).

A solution of Part C compound (14.5 mg; 0.0238 mmol) inHOAc/concentrated HCl (1.2 mL of a 9:1 solution) was stirred at 75° C.for 18 h, then was cooled to RT and concentrated in vacuo. The residuewas purified by preparative HPLC (as described for Example 1 except thata continuous gradient from 30:70 Solvent A:Solvent B to 100% B over 10min was used, followed by 4 min hold at 100% B) to give the titlecompound (7.3 mg; 53%) as a white solid.

[M+H]⁺=583.2

EXAMPLES 265-267

Examples 265-267 of the invention were prepared in a similar fashion toExample 264 using appropriately substituted phenyl oxazole mesylates.

Example # R [M + H]⁺ 265

583.1 266

587.1 267

587.1

EXAMPLE 268

A mixture of Example 229 Part C compound (70 mg; 0.28 mmol)

and 2-chloro-4-methyl-pyrimidine (36 mg; 0.28 mmol) and iPr₂NEt (97.5μL; 0.56 mmol) in toluene (2.3 mL) was stirred at 80° C. for 2 h, thenwas cooled to RT and partitioned between EtOAc (15 mL) and aqueous 1 MHCl (10 mL). The organic phase was washed with H₂O (2×15 mL) and brine(20 mL), dried (MgSO₄) and concentrated in vacuo. The residue waschromatographed (SiO₂; continuous gradient from 90% hex to 100% EtOAc)to give Part A compound (82 mg; 86%) as a colorless oil.

A mixture of Part A compound (15 mg; 0.044 mmol), Example 264 Part Bcompound (23.3 mg; 0.0748 mmol) and K₂CO₃ (10.9 mg; 0.0792 mmol) inCH₃CN (1.0 mL) was stirred at 90° C. for 30 h, then was cooled to RT andpartitioned between EtOAc (10 mL) and H₂O (5 mL). The organic phase waswashed with brine (20 mL), dried (MgSO₄) and concentrated in vacuo togive crude Part B compound, which was used in the next step withoutfurther purification.

A solution of crude Part B compound in HOAc/concentrated HCl (1.0 mL ofa 9:1 solution) was stirred at 75° C. for 18 h, then was cooled to RTand concentrated in vacuo. The residue was purified by preparative HPLC(as described for Example 1 except that a continuous gradient from 30:70Solvent A:Solvent B to 100% B over 10 min was used, followed by 4 minhold at 100% B) to give the title compound (3.8 mg; 16% for 2 steps) asa white solid.

[M+H]⁺=529.1

EXAMPLE 269-270

Example 269-270 of the invention were prepared in the same ways asExample 268 using appropriate mesylates (synthesized as for Example 264Part B compound).

Example # R [M + H]⁺ 269

529.1 270

533.1

EXAMPLE 271

A mixture of Example 229 Part C compound (476 mg; 1.91 mmol),

isobutyl chloroformate (248 μL; 1.91 mmol) and NaHCO₃ (241 mg; 2.87mmol) in dioxane:H₂O (9.6 mL of a 2:1 solution) was stirred at RT for 3h, then was partitioned between EtOAc (150 mL) and H₂O (100 mL). Theorganic phase was washed with brine (140 mL), dried (MgSO₄) andconcentrated in vacuo. The residue was chromatographed (SiO₂; continuousgradient from 90% hex to 100% EtOAc) to give Part A compound (513 mg;77%) as a colorless oil.

A mixture of Part A compound (20 mg; 0.057 mmol), Example 264 Part Bcompound (32 mg; 0.104 mmol) and K₂CO₃ (14.2 mg; 0.104 mmol) in CH₃CN(1.0 mL) was stirred at 90° C. for 30 h, then was cooled to RT andpartitioned between EtOAc (10 mL) and H₂O (5 mL). The organic phase waswashed with brine (20 mL), dried (MgSO₄) and concentrated in vacuo togive crude Part B compound, which was used in the next step withoutfurther purification.

A solution of crude Part B compound in HOAc/concentrated HCl (1.0 mL ofa 9:1 solution) was stirred at 75° C. for 18 h, then was cooled to RTand concentrated in vacuo. The residue was purified by preparative HPLC(as described for Example 1 except that a continuous gradient from 30:70Solvent A:Solvent B to 100% B over 10 min was used, followed by 4 minhold at 100% B) to give two compounds. The compound with the shorterretention time was lyophilized from 1,4-dioxane to give the titlecompound (8.5 mg; 28%) as a white solid.

[M+H]⁺=537.3

The second compound (longer retention time) was determined to be thecorresponding epimerized trans-isomer of Example 271. This compound wasalso lyophilized from 1,4-dioxane to give Example 272 (5.8 mg; 19% fortwo steps) as a white solid.

EXAMPLE 272

[M+H]⁺=537.2

EXAMPLE 273-274

Example 273 through 274 of the invention were prepared in a similarfashion to Example 272 using appropriately substituted phenyloxazolemesylates.

Example # R [M + H]⁺ 273

537.3 274

541.2

EXAMPLE 275-276

Example 275-276 of the invention were obtained in a similar fashion toExample 272. They were determined to be the corresponding epimerizedtrans-isomers of Examples 273-274.

Example # R [M + H]⁺ 275

537.2 276

541.2

EXAMPLE 277

Example 184 Part D compound (200 mg; 0.46 mmol)

was stripped from toluene (2×10 mL), dissolved in CH₂Cl₂ (10 mL), cooledto 0° C. and α-chloroethyl chloroformate (0.16 g, 1.2 mmol) was added.The solution was heated at 56° C. for 2 h, then cooled to RT andconcentrated in vacuo. The residue was stripped from toluene, dissolvedin MeOH (5 mL) and stirred for 2 h and concentrated in vacuo. Theresidue was chromatographed (SiO₂; 9:1 CH₂Cl_(h):MeOH with 0.1% ofNH₄OH) give Part A Compound as a clear oil (0.1 g; 66%)

To a solution of Part A Compound (0.1, 0.3 mmol) in toluene (5 mL) wasadded 2-chloro-4-trifluoromethyl-pyrimidine (81 mg, 0.45 mmol) andiPr₂NEt (57 mg, 0.45 mmol). The solution was stirred for 5 h at 80° C.,then cooled to RT and concentrated in vacuo. The residue waschromatographed (SiO₂; 4:1 EtOAc:hex) to give Part B compound as a clearoil (89 mg; 80%).

A mixture of Part B compound (290 mg; 0.61 mmol) and tetrabutylammoniumfluoride (1.22 mL of a 1 M solution in THF; 1.22 mmol) in THF (3.1 mL)was stirred at RT for 3 h, after which the reaction was partitionedbetween EtOAc (60 mL) and H₂O (30 mL). The organic phase was washed withbrine (40 mL), dried (MgSO₄) and concentrated in vacuo. The residue waschromatographed (SiO₂; continuous gradient from 9:1 hex:EtOAc to 100%EtOAc) to give Part C compound (140 mg; 63%) as a colorless oil.

Part D compound was synthesized according to the general proceduredescribed for the synthesis of Example 231 Part A compound except that4-methoxybenzoyl chloride was used instead of 3-chlorobenzoyl chloride.

Part E compound was synthesized from Part D compound according to thegeneral procedure described for the synthesis of Example 23 Part Acompound.

A mixture of Part C compound (47 mg; 0.129 mmol), Part E compound (60mg; 0.193 mmol) and K₂CO₃ (36 mg; 0.258 mmol) in CH₃CN (1.5 mL) wasstirred at 90° C. for 18 h, then was cooled to RT and partitionedbetween EtOAc (10 mL) and H₂O (5 mL). The organic phase was washed withbrine (20 mL), dried (MgSO₄) and concentrated in vacuo to give crudePart F compound, which was used in the next step without furtherpurification.

A mixture of crude Part F compound and 10% Pd/C (8 mg) in MeOH (1.5 mL)was stirred under an atmosphere of H₂ (balloon) at RT for 18 h. Thecatalyst was filtered off (Celite®) and the filtrate was concentrated invacuo; the residue was purified by preparative HPLC (as described forExample 1 except that a continuous gradient from 40:60 Solvent A:SolventB to 100% B over 10 min was used, followed by 4 min hold at 100% B) togive the title compound (3.0 mg; 4% for 2 steps) as a white solid.

[M+H]⁺=583.1

EXAMPLE 278

A mixture of Example 21 Part E compound (130 mg; 0.299 mmol),phenylboronic acid (50 mg; 0.41 mmol), Cu(OAc)₂ (5 mg; 0.027 mmol), 2,6lutidine (0.5 mL) and molecular sieves (4 A) in toluene (2 mL) wasstirred at RT for 24 h in air. At this point HPLC showed that producthad been formed. The reaction mixture was filtered, and the filtrate wasconcentrated in vacuo. A solution of the residue in aceticacid/concentrated HCl (2 mL of a 3:1 solution) was stirred at 70° C. for18 h. Volatiles were removed in vacuo and the residue was purified bypreparative HPLC (as described for Example 1) to provide the titlecompound (28 mg; 19.4%) as an oil.

[M+H]⁺=483.1, [α]_(CH2Cl2) ^(589nm)=−18.3° (c=1.0; 25° C.)

¹HNMR (CDCl₃): δ 8.03-8.01 (2H, dd, J=1.8 Hz), 7.56-7.48 (3H, m),7.37-7.33 (2H, t, J=7.4 Hz), 7.26-7.24 (2H, m), 7.17-7.13 (2H, m),6.71-6.75 (3H, m), 4.27-4.18 (2H, m), 4.11-4.06 (1H, m), 3.79-3.76 (1H,dd, J=4.4 Hz), 3.62-3.58 (1H, m), 3.47-3.42 (1H, t, J=10 Hz), 3.38-3.33(1H, m), 3.14-3.07 (3H, m), 2.97-2.92 (1H, dd, J=6.1 Hz), 2.67-2.61 (1H,dd, J=4.8 Hz), 2.46 (3H, s)

EXAMPLE 279

The titled compound (41 mg; 28.4%) was prepared from Example 21 Part Ecompound (using the same sequence as the synthesis of Example previouscompound).

[M+H]⁺=483.1 [α]_(CH2Cl2) ^(589nm)=20°, (c=1.0; 25° C.)

¹HNMR (CDCl₃): δ 8.03-8.00 (2H, dd, J=1.8 Hz), 7.56-7.48 (3H, m),7.37-7.33 (2H, t, J=7.4 Hz), 7.26-7.24 (2H, m), 7.17-7.13 (2H, m),6.71-6.75 (3H, m), 4.27-4.18 (2H, m), 4.11-4.06 (1H, m), 3.79-3.76 (1H,dd, J=4.4 Hz), 3.62-3.58 (1H, m), 3.47-3.42 (1H, t, J=10 Hz), 3.38-3.34(1H, m), 3.14-3.04 (3H, m), 2.98-2.93 (1H, dd, J=6.1 Hz), 2.62-2.56 (1H,dd, J=4.8 Hz), 2.44 (3H, s)

EXAMPLE 280

A mixture of Example 21 Part E compound (50 mg; 0.115 mmol),2-Chloro-4-(trifluoromethyl)-pyrimidine (21 mg; 0.115 mmol), Et₃N (50mg; 0.5 mmol) in toluene (3 mL) was stirred at 50° C. for 1 h in air.The reaction mixture was concentrated in vacuo. A solution of theresidue in acetic acid/concentrated HCl (2 mL of a 3:1 solution) andstirred at 80° C. for 18 h. Volatiles were removed in vacuo and theresidue was purified by preparative HPLC (as described for Example 1) toprovide the title compound (60 mg; 90%) as a white solid.

[M+H]⁺=553.3, [α]_(CH2Cl2) ^(589nm)=−37.7°; (c=1.25; 25° C.)

¹HNMR (CDCl₃): δ 8.55 (1H, s), 8.01-7.99 (2H, d, J=8 Hz), 7.53-7.46 (3H,m), 7.12-7.21 (1H, m), 6.84-6.69 (4H, m), 4.17-4.27 (2H, t, J=8 Hz),3.98-4.08 (1H, m), 3.50-3.80 (3H, m), 3.18-3.30 (1H, m), 3.03-3.13 (2H,t, J=8 Hz), 2.77-2.96 (2H, m), 2.57-2.67 (1H, m), 2.44 (3H, s)

EXAMPLE 281

A mixture of Example 12 Part C compound (550 mg; 0.92 mmol) and 10% Pd/C(30 mg) in MeOH (10 mL) under an atmosphere of H₂ was stirred at RT for2 h. At this point analytical HPLC showed that the reaction wascomplete. The catalyst was filtered off (using a pad of Celite®) and thefiltrate was concentrated in vacuo to give crude Part A compound as anoil which was used in the next reaction without further purification.

A mixture of crude Part A compound and di-tert butyl dicarbonate (300mg; 1.3 mmol) in saturated aqueous NaHCO₃ (5 mL) and THF (5 mL) wasstirred at RT for 2 h, then was partitioned between EtOAc and H₂O (20 mLeach). The organic phase was concentrated in vacuo and the residue waspurified by preparative HPLC (as described for Example 1) to give thetitle compound (237 mg; 52% for 2 steps) as an oil.

Step 1. Preparation of Diazomethane:To a solution of aqueous KOH (40%; 2 mL) and diethyl ether (5 mL) wasadded 1-Methyl-3-nitro-1-nitrosoguanidine (176 mg; 1.2 mmol) slowly at0° C. and the reaction was stirred at 0° C. for a further 30 min. Theaqueous phase was removed and the top yellow organic phase containingdiazomethane was dried with solid KOH (1 g) at 0° C. and was used forthe next step without further purification.Step 2. Preparation of Diazoketone:To a solution of Part B compound (237 mg; 0.48 mmol) in THF (10 mL) andN-methylmorpholine (61 mg; 0.6 mmol) was cooled to −20° C. and addedisobutyl chloroformate (82 mg; 0.6 mmol) over 5 min. The reaction wasstirred at −20° C. for a further 30 min and then was added to thesolution of CH₂N₂ (from Step 1) at 0° C. After stirring at 0° C. for 30min, the reaction was stirred at RT for another 3 h, then wasconcentrated in vacuo; the residue was chromatographed (SiO₂; 3:1Hex:EtOAc) to give Part C compound (150 mg; 60%) as an oil.

To a solution of Part C compound (150 mg; 0.29 mmol) in anhydrous MeOH(1 mL) was added a solution of silver benzoate (15 mg; 0.065 mmol) inEt₃N (0.7 mL) and the reaction was stirred at RT for 30 min, after whichEtOAc (10 mL) was added. The solution was washed with 1N aqueous HCl (5mL) and H₂O (5 mL×2), dried (Na₂SO₄) and concentrated in vacuo. Theresidue was chromatographed (SiO₂; 3:1 Hex:EtOAc) to give Part Dcompound (78 mg; 31%) as an oil.

A solution of Part D compound (78 mg; 0.15 mmol) and TFA (1 mL) inCH₂Cl₂ (1 mL) was stirred at RT for 30 min. Volatiles were removed invacuo and the residue was purified by preparative HPLC (as described forexample 1) to give Part E compound (80 mg; 99%).

To a 0° C. solution of Part E compound (10 mg; 0.018 mmol) and DMAP (12mg; 0.1 mmol) in CH₂Cl₂ (1 mL) was added dropwise ethyl chloroformate (4μL; 0.032 mmol). The reaction mixture was allowed to warm to RT andstirred at RT for 3 h. At this point HPLC indicated that all startingmaterial had been consumed. The solid was filtered through SiO₂ withHex:EtOAc (3:1) and the filtrate was concentrated in vacuo to give theCartg (SiO₂; Hex:EtOAc 3:1) to provide crude Part F compound as an oil.

A solution of Part F compound in aqueous LiOH (1 mL of a 1 M solution)and THF (1 mL) was stirred at RT for 2 h; TLC indicated that thereaction was complete at this point. The reaction mixture was acidifiedwith aqueous HCl (2 mL of a 1 M solution) and extracted with EtOAc (2×2mL). The organic phase was washed with H₂O (2×2 mL) and concentrated invacuo. The residue was purified by preparative HPLC (as described forExample 1) to provide the title compound (7.4 mg; 85.9%) as an oil.

[M+H]⁺=479.2

EXAMPLES 282-288

Examples 282 through 288 were prepared in a similar fashion to theprevious Example using the appropriate chloroformates.

Example # R [M + H]⁺ 282

491.3 283

493.3 284

507.3 285

527.2 286

545.2 287

557.2 288

541.2

EXAMPLE 289

A mixture of Example 36 Part B compound (2 g; 2.77 mmol), Example 1 PartB compound (0.8 g; 3.0 mmol) and TFA (1 drop) in CH₂Cl₂ (10 mL) wasstirred at RT for 3 h, then was concentrated in vacuo. The residue waschromatographed (SiO₂; hex:EtOAc 1:1) to give Part C compound (1.66 g;64%) as an oil.

To a −78° C. solution of Part A compound (2.5 g; 5.05 mmol) in CH₂Cl₂(10 mL) was added CH₃CHClOCOCl (0.5 mL; 4.45 mmol) The reaction mixturewas stirred at −78° C. for 30 min, then was allowed to warm to RT andstirred at RT for 1 h. At this point, HPLC indicated that all startingmaterial had been consumed. Volatiles were removed in vacuo and MeOH (10mL) was added; the solution was then stirred at RT for 8 h. Volatileswere removed in vacuo to give crude Part B compound, which was used inthe next step without further purification.

A solution of crude Part B compound and di-tert butyl dicarbonate (800mg; 3.66 mmol) in saturated aqueous NaHCO₃ (10 mL) and THF (10 mL) wasstirred at RT for 2 h, then was partitioned between EtOAc and H₂O (20mL). The organic phase was concentrated in vacuo and the residue waschromatographed (SiO₂; Hex:EtOAc 3:1) to give Part C compound (2.1 g;82% for two steps) as an oil.

To a −70° C. solution of Part C compound (373 mg; 0.74 mmol) inanhydrous THF (3 mL) was added DIBALH (1.5 mL of a 1 M solution inhexane; 1.5 mmol) dropwise. The reaction was stirred at −70° C. for 20min, then was warmed to RT and stirred at RT for 2 h, then re-cooled to−70° C. and quenched by dropwise addition of MeOH (1 mL). The mixturewas allowed to warm to RT, aqueous Rochelle salt (10 mL of a 1 Msolution) was added and stirring was continued for 1 h. The mixture waspartitioned between H₂O and Et₂O (20 mL each). The aqueous phase wasextracted with additional Et₂O (20 mL); the combined organic extractswere dried (Na₂SO₄) and concentrated in vacuo to give crude Part Dcompound, which was used in the next step without further purification.

To a 0° C. solution of crude Part C compound and Ph₃P (232 mg; 0.89mmol) in CH₂Cl₂ (1 mL) was added CBr₄ (294 mg; 0.89 mmol) portionwise.The reaction was allowed to warm to RT and stirred at RT for 2 h, thenwas concentrated in vacuo. The residue was chromatographed (SiO₂;hex:EtOAc 3:1) to give Part E compound (270 mg; 68% for two steps) as anoil.

A mixture of Part E compound (270 mg; 0.5 mmol), (Ph₃P)₄Pd^(o) (58 mg;0.05 mmol) and KHCO₃ (200 mg; 2.0 mmol) in anhydrous MeOH (5 mL) in anautoclave was pressurized to 100 psi with carbon monoxide (vesselflushed 3× with CO). The reaction mixture was stirred at RT for 3 h,after which the CO gas was released and the mixture was filtered. Thefiltrate was concentrated in vacuo and the residue was chromatographed(SiO₂; 3:1 hex:EtOAc) to give Part F compound (150 mg; 56%) as an oil.

A suspension of Part F compound (150 mg; 0.29 mmol) and 10% Pd/C (10 mg)in MeOH (5 mL) was stirred at RT under an atmosphere of H₂ (balloon) for2 h. The catalyst was filtered off (Celite®) and the filtrate wasconcentrated in vacuo to give the Part G compound (147 mg; 56% for 2steps) as an oil.

The two enantiomers of racemic Part G compound (147 mg; 0.283 mmol) wereseparated by preparative HPLC using the following conditions:ChiralPAK@AS 5 cm×50 cm chiral column: flow rate=40 mL/min; isocraticconditions=93:7 isopropanol:hexane. Chiral analytical HPLC (DaicelChiralcel AS 4.6×250 mm column): flow rate=1.5 mL/min; isocraticconditions=80:20 hexane:iPrOH; detector wavelength=220 nm. Part Gcompound (Enantiomer I) was obtained (60 mg; 81.6%; retention time=4.64min; ee>95%) as an oil. Part H compound (Enantiomer II) was obtained (55mg; 74.8%; retention time=6.29 min; ee>90%) as an oil.

A solution of Part H compound (enantiomer I; 60 mg; 0.115 mmol) in TFA(0.5 mL) and CH₂Cl₂ (0.5 mL) was stirred at RT for 2.5 h, then wasconcentrated in vacuo to give crude Part J compound as an oil, which wasused in the next step without further purification.

A mixture of crude Part J compound (0.038 mmol), DMAP (30 mg; 0.3 mmol)and n-propyl chloroformate (36 mg; 0.3 mmol) in CH₂Cl₂ (1 mL) wasstirred at RT for 1 h, then was loaded onto a SiO₂ cartridge and flushedwith EtOAc/Hexane (1:3) to give crude Part K compound.

A solution of Part K compound in aqueous LiOH (1 mL of a 1 M solution)and THF (1 mL) was stirred at RT for 2 h; TLC indicated that thereaction was complete at this point. The reaction mixture was acidifiedwith aqueous HCl (2 mL of a 1 M solution) and extracted with EtOAc (2mL). The organic phase was washed with H₂O (2×2 mL) and concentrated invacuo. The residue was purified by preparative HPLC (as described forExample 1) to provide the title compound (28 mg; 95%) as an oil.

[M+H]⁺=493.2, [α]_(CH2Cl2) ^(589nm)=25.5; (c=0.65; 25° C.)

¹HNMR (CDCl₃): δ 8.02-8.0 (2H, dd, J=8 Hz), 7.6-7.46 (3H, m), 7.23-7.19(1H, t, J=12 Hz), 6.78-6.65 (3H, m), 4.3-4.07 (4H, m), 3.85-3.52 (4H,m), 3.20-3.1 (1H, m), 3.09-3.01 (2H, t, J=6.2 Hz), 2.98-2.89 (1H, m),2.44 (3H, s), 2.20-2.11 (1H, m), 1.96-1.85 (1H, m), 1.74-1.62 (2H, m),0.97-0.95 (3H, m)

EXAMPLES 290-292

Example 290 was prepared from Example 289 Part J compound in the sameway as Example 289 but using isobutyl chloroformate. Examples 2-3 wereprepared from Example 289 Part I compound using the identical sequenceas for the synthesis of Example 289 from Example 289 Part H compound,using n-propyl and isobutyl chloroformate respectively. [α] 589 nm inExample # Structure CH₂Cl₂ [M + H]⁺ 290

28.2 (c = 0.95) 507.3 291

−21.3 (c = 0.95) 493.3 292

−28.5 (c = 0.8) 507.3

EXAMPLE 293

A mixture of Example 2 Part B compound (250 mg; 0.522 mmol), phosgene (5mL of a 1M solution in CH₂Cl₂) and catalytic DMF was stirred at 60° C.in a sealed tube for 18 h, then was concentrated in vacuo to give crudePart A compound which was used in the next step without furtherpurification.

To a 0° C. solution of Part A compound in CH₂Cl₂ (2 mL) was addeddiazomethane (prepared as for Example 281 Part C). The reaction wasstirred at 0° C. for 30 min, then at RT for another 3 h. Volatiles wereremoved in vacuo and the residue was chromatographed (SiO₂;Hex:EtOAc=3:1) to give Part B compound (180 mg; 57% for 2 steps) as ayellow oil.

To a solution of Part B compound (180 mg; 0.36 mmol) in anhydrous MeOH(4 mL) was added a solution of PhCO₂Ag (146 mg; 0.7 mmol) in Et₃N (5 mL)and the reaction was stirred at RT for 30 min, after which the reactionwas partitioned between EtOAc (5 mL) and 1N aqueous HCl (5 mL×1). Theorganic phase was washed with H₂O (5 mL×2), dried (Na₂SO₄) andconcentrated in vacuo to give crude Part C compound.

A solution of crude Part D compound in aqueous LiOH.H₂O (1 mL of a 1 Msolution) and THF (2 mL) was stirred at RT for 3 h; TLC indicated thatthe reaction was complete at this point. The reaction mixture wasacidified with aqueous HCl (2 mL of a 1 M solution) and extracted withEtOAc (2 mL). The organic phase was washed with H₂O (2×2 mL) andconcentrated in vacuo. The residue was purified by preparative HPLC (asdescribed for Example 1) to provide the title compound (160 mg; 90% fortwo steps) as an oil.

[M+H]⁺=493.2

¹HNMR (CDCl₃): δ 8.03-8.0 (2H, m), 7.56-7.51 (3H, m), 7.19-7.15 (1H, m),6.76-6.70 (3H, m), 4.24-4.21 (2H, m), 4.12-4.07 (2H, q, J=7.0 Hz),3.83-3.74 (1H, m), 3.53-3.41 (1H, m), 3.13-3.01 (4H, m), 2.83-2.77 (1H,m), 2.55-2.43 (2H, m), 2.40 (3H, s), 2.34-2.13 (3H, m), 1.27-1.19 (3H,m)

EXAMPLE 294

The title compound (16 mg; 32%) was prepared from Example 3 compound(using the same sequence as for the synthesis of Example 293 except thatphenyl chloroformate was used instead of ethyl chloroformate).

[M+H]⁺=541.3

¹HNMR (CDCl₃): δ 8.03-8.00 (2H, m), 7.56-7.49 (3H, m), 7.33-7.28 (2H,m), 7.19-7.15 (2H, m), 7.08-7.05 (2H, m), 6.75-6.71 (3H, m), 4.25-4.23(2H, t, J=5 Hz), 3.98-3.85 (1H, m), 3.70-3.58 (1H, m), 3.31-3.13 (2H,m), 3.11-3.09 (2H, t, J=5 Hz), 2.86-2.80 (1H, m), 2.61-2.57 (2H, m),2.48 (3H, s), 2.34-2.13 (3H, m)

EXAMPLE 295

The title (15 mg; 42% yield overall for 3 steps) was prepared fromExample 22 compound by the same sequence as for the synthesis of Example293.

[M+H]⁺=493.2; [α]_(CH2Cl2) ^(589nm)=−16.1° (c=0.6; 25° C.)

¹HNMR (CDCl₃): δ 8.03-8.02 (2H, m), 7.56-7.51 (3H, m), 7.19-7.15 (1H,m), 6.76-6.70 (3H, m), 4.25-4.22 (2H, t, J=5.72 Hz), 4.13-4.08 (2H, m),3.57-3.53 (1H, m), 3.33-3.09 (6H, m), 2.75-2.07 (8H, m), 1.25-1.22 (3H,m)

EXAMPLE 296

A solution of DL-pyroglutamic acid (5 g; 0.039 mol, HClO₄ (1.25 mL of a70% solution) in tert-butyl acetate (60 mL) was stirred at RT for 18 h,then was poured into saturated aqueous NaHCO₃ (100 mL) and ice. Themixture was extracted with EtOAc (20 mL×3). The combined organicextracts were dried (Na₂SO₄) and concentrated in vacuo to give Part Acompound as white crystals (4.36 g; 60.3%).

A mixture of Part A compound (4.36 g; 23.5 mmol); di-tert-butyldicarbonate (10.7 g; 50 mmol) and DMAP (6.1 g; 50 mmol) in MeCN (20 mL)was stirred at RT for 18 h. Volatiles were removed in vacuo and theresidue was chromatographed (SiO₂; Hex:EtOAc 1:1) to give part Bcompound (6.6 g; 98.4%) as an oil.

A mixture of 3-hydroxybenzyl alcohol (2 gm; 16 mmol), the mesylateExample 23 Part A compound (2.0 g; 7.11 mmol)

and K₂CO₃ (5.0 g; 36 mmol) in MeCN (100 mL) was stirred at 80° C. for 10h. At this point LC/MS showed that the reaction was complete. Thereaction was cooled to RT, solids were filtered off, and the filtratewas partitioned between EtOAc (100 mL) and aqueous 1 M HCl (10 mL). Theorganic phase was successively washed with 1 M NaOH (10 mL) and H₂O (50mL), dried (Na₂SO₄) and concentrated in vacuo. The residue waschromatographed (SiO₂; 2:1 Hex:EtOAc) to give Part C compound (2.15 g;98%) as white crystals.

A mixture of Part C compound (2.15 g; 6.95 mmol), PBr₃ (10 mL of a 1 Msolution in CH₂Cl₂) in CH₂Cl₂ (5 mL) was stirred at RT for 0.5 h.Volatiles were removed in vacuo. The residue was chromatographed (SiO₂;Hex:EtOAc 3:1) to give part D compound (2.0 g; 75%) as white crystals.

To a −74° C. solution of Part B compound (200 mg; 0.7 mmol) in THF (5mL) was added LiN(TMS)₂ (1.2 mL of a 1 M solution in THF) dropwise. Thereaction was stirred at −74° C. for 40 min, after which a solution ofPart D compound (200 mg; 0.54 mmol) in THF (5 mL) was added dropwise at−60° C. The reaction mixture was stirred at −60° C. for 2 h, then wasquenched by dropwise addition of saturated aqueous NH₄Cl (1 mL). Themixture was allowed to warm to RT, then extracted with EtOAc (2×10 mL).The combined organic extracts were washed with water, dried (Na₂SO₄),concentrated in vacuo and the crude residue was chromatographed (SiO₂;Hex:EtAc 3:1) to give both the desired cis isomer (27 mg; 6.5%) Part Ecompound as well as the trans isomer Part F compound (8.7 mg; 2.4%) asoils.

To a −74° C. solution of Part E compound (cis isomer; 27 mg; 0.047 mmol)in THF (5 mL) under N₂ was added LiEt₃BH (0.06 mL of a 1 M solution inTHF). The reaction was stirred at −74° C. for 30 min, then was quenchedby dropwise addition of saturated aqueous NaHCO₃ (1 mL) and one drop ofH₂O₂. The mixture was allowed to warm to RT, then extracted with EtOAc(2×10 mL). The combined organic extracts were washed with water, dried(Na₂SO₄) and concentrated in vacuo. To a −74° C. solution of the crudeproduct and Et₃SiH (7.5 μL; 1M solution in THF; 0.06 mmol) in CH₂Cl₂ (5mL) was added BF₃.OEt₂ (7.6 μL; 0.06 mmol). The reaction was stirred at−74° C. for 30 min, after which more Et₃SiH (7.5 μL) and BF₃—OEt₂ (7.6μL) was added. The reaction was warmed to RT and stirred at RT foranother 30 min, after which it was quenched by dropwise addition ofsaturated aqueous NaHCO₃ (1 mL), then extracted with CH₂Cl₂ (2×10 mL).The combined organic extracts were dried with Na₂SO₄ and concentrated invacuo. The residue was chromatographed (SiO₂; Hex:EtOAc 2:1) to providePart G compound (23 mg, 80%).

A solution of Part H compound and TFA (1 mL) in CH₂Cl₂ (1 mL) wasstirred at RT for 1 h, after which volatiles were removed in vacuo togive crude Part H compound (15 mg; 79%), which was used in the next stepwithout further purification.

A solution of crude Part I compound, saturated aqueous NaHCO₃ (2 mL) andphenyl chloroformate (50 μL; 0.36 mmol) in THF (2 mL) was stirred at RTfor 30 min, then was partitioned between EtOAc and H₂O (10 mL each). Theorganic phase was dried (MgSO₄) and concentrated in vacuo. The residuewas purified by preparative HPLC (as described for Example 1) to providethe title compound (19 mg; 76.7%) as an oil.

[M+H]⁺=527.3

¹HNMR (CDCl₃): δ 7.98-7.94 (2H, m), 7.49-7.10 (9H, m), 6.75-6.68 (3H,m), 4.54-4.20 (3H, m), 3.88-3.74 (1H, m), 3.57-3.42 (1H, m), 3.02-2.99(2H, t, J=5 Hz), 2.83-2.74 (2H, m), 2.58-2.50 (1H, m), 2.40-2.33 (4H,m), 2.02-1.92 (1H, m)

EXAMPLE 297

This trans isomer (6.6 mg; 83.5%) was prepared from Part F compound(using the same sequence as for the synthesis of previous Cis isomer).

[M+H]⁺=527.3

¹HNMR (CDCl₃): δ 8.03-7.98 (2H, m), 7.56-7.47 (3H, m), 7.35-7.27 (2H,m), 7.22-7.05 (4H, m), 6.75-6.69 (3H, m), 4.61-4.49 (1H, m), 4.23-4.20(2H, t, J=8.0 Hz), 3.79-3.70 (1H, m), 3.29-3.20 (1H, m), 3.09-3.06 (2H,t, J=8 Hz), 2.78-2.60 (3H, m), 2.45 (3H, s), 2.40-1.92 (2H, m)

EXAMPLE 298

A mixture of N-benzoyl-L-tyrosine ethyl ester (1.0 g; 3.19 mmol),5-phenyl-2-methyl-oxazole-4-ethanol (650 mg; 3.19 mmol) andcyanomethylene-tri-n-butylphosphorane (1.15 g; 4.79 mmol) in toluene (10mL) was stirred at 70° C. for 3 h, then was concentrated in vacuo. Theresidue was chromatographed (SiO₂; Hex:EtAc 2:1) to provide Part Acompound (1.28 g; 81%) as yellowish crystals.

A solution of Part A compound (500 mg; 1.0 mmol), LiAlH₄ (2 mL of a 1 Msolution in THF) in THF was stirred at 50° C. for 1 h, then MeOH (1 mL)was added slowly, follow by aqueous Rochelle salt (5 mL of a 1 Msolution). The mixture was stirred at RT for 18 h and filtered. Thefiltrate was diluted with Et₂O (20 mL) and washed with H₂O (3×30 mL),dried (MgSO₄) and concentrated in vacuo to give Part B compound (394 mg;89%) as white solid.

A solution of Part B compound (300 mg; 0.68 mmol), acrylonitrile (4.3mL) and HOAc (41 μL) in EtOH (5 mL) was stirred at 75° C. for 30 h, thenwas cooled to RT and partitioned between EtOAc (20 mL) and aqueous NaOH(10 mL of a 1 M solution). The organic phase was washed with H₂O (2×30mL), dried (MgSO₄) and concentrated in vacuo. The crude residue waschromatographed (SiO₂; 2:1 Hex:EtOAc) to give Part C compound (180 mg;89%) as an oil.

A mixture of Part C compound (182 mg; 0.367 mmol) and SOCl₂ (0.25 mL;3.4 mmol) in CHCl₃ (5 mL) was heated at reflux for 30 min, then wascooled to RT. 100 mL Et₂O was added and the mixture was filtered; therecovered solids were dried in vacuo to give Part D compound (200 mg;99%) as white solid.

To a RT solution of Part D compound (200 mg; 0.36 mmol) in THF (5 mL)under N₂ was added dropwise NaN(TMS)₂ in THF (0.80 mL of a 1 M solution;0.80 mmol). The reaction was stirred at RT for 1 h, then was quenched byaddition of saturated aqueous NH₄Cl (1 mL). The mixture was extractedwith EtOAc (10 mL). The organic phase was washed with water (2×10 mL),dried (Na₂SO₄) and concentrated in vacuo. The crude residue waschromatographed (SiO₂; 2:1 Hex:EtOAc) to give Part E compound (21 mg;24%) as an oil in addition to the trans isomer Part F compound (21 mg;24%)

A mixture of Part E compound (21 mg; 0.044 mmol) in H₂SO₄—MeOH (10%; 2mL) was stirred at 80° C. for 72 h, then was cooled to RT, the mixturewas partitioned between EtOAc and H₂O (10 mL each). The organic phasewas washed with H₂O (2×10 mL), dried (Na₂SO₄) and concentrated in vacuo.The crude residue was chromatographed (SiO₂; 1:1 Hex:EtOAc) to give PartG compound (20 mg; 89%) as an oil.

Part H compound (20 mg; 89%) was prepared from Part F compound (usingthe same procedure as the preparation of Part G compound from Part Ecompound) as an oil.

Part I compound (18 mg; 80%) and Part J compound (19 mg; 82%) were bothprepared from N-benzoyl-D-tyrosine ethyl ester (using exactly the samesequence as the synthesis of Part G compound and Part H compound).

A solution of Part G compound (20 mg; 0.039 mmol) and CH₃CHClOCOCl (5μL; 0.05 mmol) in CH₂Cl₂ (2 mL) was stirred at RT for 18 h. Volatileswere removed in vacuo and MeOH (2 mL) was added; the solution was thenstirred at RT for 8 h. Volatiles were removed in vacuo and the residuewas purified by preparative HPLC (YMC reverse-phase ODS 30×250 mmcolumn; flow rate=25 mL/min; 30 min continuous gradient from 30:70 B:Ato 100% B+10 min hold-time at 100% B, where solventA=90:10:0.1H₂O:MeOH:TFA and solvent B=90:10:0.1 MeOH:H₂O:TFA) to providePart K compound (16 mg; 80%) as a TFA salt.

A mixture of Part K compound (16 mg; 0.038 mmol),2-Chloro-4-(trifluoromethyl)-pyrimidine (10 mg; 0.04 mmol) and Et₃N (25mg; 0.25 mmol) in toluene (2 mL) was stirred at 60° C. for 2 h, then wascooled to RT and concentrated in vacuo. A solution of the residue inHOAc/concentrated HCl (5 mL of a 3:1 solution) was stirred at 75° C. for18 h. Volatiles were removed in vacuo and the residue was purified bypreparative HPLC (as described for Example 1) to provide the titlecompound (5.4 mg; 30%) as a white solid.

[M+H]⁺=553.2

¹HNMR (CDCl₃): δ 8.50-8.49 (1H, d, J=4 Hz), 7.91-7.90 (2H, m), 7.40-7.30(3H, m), 7.09-7.07 (2H, d, J=8 Hz), 6.78-6.73 (3H, m), 4.28 (1H, s,broad), 4.15-4.13 (2H, t, J=4 Hz), 4.00 (1H, s, br), 3.85 (1H, s, br),3.28-3.26 (1H, d, J=8 Hz), 3.07-3.05 (1H, m), 2.98-2.92 (2H, t, J=4 Hz),2.45 (1H, s, br), 2.32 (3H, s), 2.24-2.16 (2H, m)

Chiral analytical HPLC (Daicel Chiralcel AD 4.6×250 mm column): flowrate=1 mL/min; isocratic conditions=100:7 A:B, where A=heptane+0.1% TFA;B IPA+0.1% TFA; detector wavelength=220 nm; retention time=23 min;ee>90%

EXAMPLE 299

Part A compound was prepared from Example 298 Part H compound in exactlythe same way as Example 298 Part K compound was prepared from Example298 Part G compound.

The title compound (6.9 mg; 42% overall for 3 steps) was prepared fromPart A compound in exactly the same way as Example 298 compound wasprepared from Example 298 Part K compound.

[M+H]⁺=553.3

¹HNMR (CDCl₃): δ 8.61-8.60 (1H, d, J=4 Hz), 8.03-8.01 (2H, d, J=8 Hz),7.60-7.50 (3H, m), 7.12-7.10 (2H, d, J=8 Hz), 6.88-6.87 (1H, m),6.82-6.81 (2H, d, J=8 Hz) 4.50 (1H, s, broad), 4.15-4.13 (2H, t, J=4.8Hz), 3.82-3.81 (2H, d, J=7.0 Hz), 3.13-3.10 (4H, m), 2.61 (1H, S,broad), 2.48 (3H, s), 2.18-2.16 (2H, m)

Chiral analytical HPLC (Daicel Chiralcel OD 4.6×500 mm column): flowrate=1 mL/min; isocratic conditions=93:7 A:B, where A=heptane+0.1% TFA;B IPA+0.1% TFA; detector wavelength=220 nm; retention time=32 min;ee>90%

EXAMPLE 300

Part A compound was prepared from Example 298 Part I compound accordingto the method used to prepare Example 298 Part K compound from Example298 Part G compound.

The title compound (11.7 mg; 66% overall for 3 steps) was prepared fromPart A compound (using the same sequence as for the synthesis of Example299 compound).

[M+H]⁺=553.3

¹HNMR (CDCl₃): δ 8.57-8.56 (1H, d, J=4 Hz), 7.99-7.97 (2H, m), 7.44-7.38(3H, m), 7.16-7.15 (2H, d, J=8 Hz), 6.83-6.82 (3H, m), 4.35 (1H, s,broad), 4.23-4.20 (2H, t, J=8 Hz), 4.07 (1H, s, broad), 3.94 (1H, s,broad), 3.36-3.33 (1H, d, J=8 Hz), 3.18-3.11 (1H, m), 3.02-3.00 (2H, m),2.50 (1H, s, broad), 2.39 (3H, s), 2.30-2.20 (2H, m)

Chiral analytical HPLC (Daicel Chiralcel AD 4.6×250 mm column): flowrate=1 mL/min; isocratic conditions=90:10 A:B, where A=heptane+0.1% TFA;B IPA+0.1% TFA; detector wavelength=220 nm; retention time=13.45 min;ee>90%

EXAMPLE 301

Part A compound was prepared from Example 298 Part J compound accordingto the method used to prepare Example 298 Part K compound from Example298 Part G compound.

The title compound (4.4 mg; 50% overall for 3 steps) was prepared fromPart A compound (using the same sequence as for the synthesis of Example299).

[M+H]⁺=553.3

¹HNMR (CDCl₃): δ 8.61-8.60 (1H, d, J=4 Hz), 8.03-8.01 (2H, d, J=8 Hz),7.58-7.50 (3H, m), 7.12-7.10 (2H, d, J=8 Hz), 6.88-6.87 (1H, m),6.83-6.81 (2H, d, J=8 Hz) 4.50 (1H, s, broad), 4.23-4.21 (2H, t, J=4.8Hz), 3.82-3.81 (2H, d, J=7.0 Hz), 3.13-3.10 (4H, m), 2.61 (1H, s,broad), 2.47 (3H, s), 2.18-2.16 (2H, m)

Chiral analytical HPLC (Daicel Chiralcel OD 4.6×500 mm column): flowrate=1 mL/min; isocratic conditions=93:7 A:B, where A=heptane+0.1% TFA;B IPA+0.1% TFA; detector wavelength=220 nm; retention time=39 min;ee>90%

EXAMPLE 302

A suspension of Example 298 Part G compound (34 mg; 0.066 mmol) andPd-Black (20 mg) in HCO₂H—MeOH (3 mL of a 9:1 solution) was stirred atRT for 1 h. The catalyst was filtered off and the filtrate waspartitioned between EtOAc (5 mL) and aqueous NaOH (2 mL of a 1 Msolution). The organic phase was washed with water, dried, (Na₂SO₄) andconcentrated in vacuo to give Part A compound (27 mg; 97.2%) as an oilwhich was used in the next step without further purification.

A mixture of Part A compound (18 mg; 0.042 mmol), DMAP (12 mg; 0.1 mmol)and phenyl chloroformate (15 μL; 0.12 mmol) in CH₂Cl₂ (1 mL) was stirredat RT for 2 h, then was partitioned between aqueous 1 N HCl and EtOAc.The organic phase was washed with H₂O and brine, dried (MgSO₄) andconcentrated in vacuo. A mixture of the residual crude carbamate-esterin HOAc/concentrated HCl (5 mL of a 4:1 solution) was stirred at 80° C.for 18 h, then was cooled to RT and concentrated in vacuo. The mixturewas partitioned between EtOAc and H₂O (5 mL each). The organic phase wasconcentrated in vacuo and the residue was purified by preparative HPLC(as described for Example 1) to give the title compound (11.6 mg; 71%)as a white solid.

[M+H]⁺=527.1

¹HNMR (CDCl₃): δ 7.99-7.97 (2H, m), 7.47-7.43 (3H, m), 7.40-7.3 (2H, m),7.25-7.10 (5H, m), 6.82-6.80 (2H, d, J=8 Hz), 4.50-4.10 (3H, m),4.05-3.90 (1H, m), 3.75-3.63 (1H, m), 3.29-3.19 (1H, m), 3.18-3.01 (3H,m), 2.74-2.50 (1H, m), 2.40 (3H, s), 2.26-2.10 (2H, m)

Chiral analytical HPLC (Daicel Chiralcel OD 10 um 4.6×250 mm column):flow rate=1.0 mL/min; isocratic conditions=85:15 A:B, where A=hexanewith 0.1% TFA; B=isopropanol with 0.1% TFA; detector wavelength=220 nm;retention time=12.39 min; ee>90%

EXAMPLE 303

The title compound (12 mg; 78%) was prepared from Example 302 Part Acompound (using the same sequence as for the synthesis of Example 302except that ethyl chlorformate was used instead of phenylchloroformate).

[M+H]⁺=479.2

¹HNMR (CDCl₃): δ 7.99-7.97 (2H, d, J=8 Hz), 7.52-7.45 (3H, m), 7.06 (2H,s), 6.80-6.78 (2H, d, J=8 Hz), 4.21-4.14 (4H, m), 4.01-3.79 (2H, m),3.52-3.47 (1H, t, J=8 Hz), 3.32-2.85 (4H, m), 2.56-2.47 (1H, m), 2.42(3H, s), 2.23-1.89 (2H, m), 1.30-1.27 (3H, t, J=8 Hz)

Chiral analytical HPLC (Daicel Chiralcel AD 10 um 4.6×250 mm column):flow rate=1.0 mL/min; isocratic conditions=90:10 A:B, where A=hexanewith 0.1% TFA; B=isopropanol with 0.1% TFA; detector wavelength=220 nm;retention time=20.43 min; ee>90%

EXAMPLE 304

The title Compound (15.6 mg; 70%) was prepared from Example 299 Part Acompound using the same sequence as for the synthesis of Example 302from Example 302 Part A compound.

[M+H]⁺=527.1

¹HNMR (CDCl₃): δ 7.98-7.97 (2H, d, J=8 Hz), 7.45-7.29 (5H, m), 7.23-7.02(5H, m), 6.85-6.82 (2H, d, J=8 Hz), 4.45-4.20 (3H, m), 3.82-3.56 (2H,m), 3.08-2.85 (4H, m), 2.62-2.80 (1H, m), 2.37 (3H, s), 2.13-2.03 (2H,m)

Chiral analytical HPLC (Daicel Chiralcel OD 10 um 4.6×250 mm column):flow rate=1.0 mL/min; isocratic conditions=85:15 A:B, where A=hexanewith 0.1% TFA; B=isopropanol with 0.1% TFA; detector wavelength=220 nm;retention time=18.18 min; ee>90%

EXAMPLE 305

Part A compound (37 mg; 90%) was prepared from Example 298 Part Hcompound by the same procedure as the synthesis of Example 302 Part Acompound from Example 298 Part G compound.

The title compound (16 mg; 79%) was prepared according to the sameprocedure as the synthesis of Example 303 from Example 302 Part Acompound.

[M+H]⁺=479.2

¹HNMR (CDCl₃): δ 8.00-7.97 (2H, m), 7.50-7.45 (3H, m) 7.05 (2H, s),6.81-6.79 (2H, d, J=8 Hz), 4.21-4.11 (5H, m), 3.65-3.48 (2H, m),3.06-2.51 (5H, m), 2.42 (3H, s), 2.08-1.95 (2H, m), 1.29-1.26 (3H, t,J=4 Hz)

Chiral analytical HPLC (Daicel Chiralcel AD 10 um 4.6×250 mm column):flow rate=1.0 mL/min; isocratic conditions=90:10 A:B, where A=hex with0.1% TFA; B=IPA with 0.1% TFA; detector wavelength=220 nm; retentiontime=27.23 min; ee>90%

EXAMPLE 306

Part A compound (39 mg; 97%) was prepared from Example 298 Part Icompound by the same procedure as Example Part A compound.

The title compound was prepared (12 mg; 47%) was prepared from Part Acompound using the same procedure as for the synthesis of Example 302from Example 302 Part A compound.

[M+H]⁺=527.1

¹HNMR (CDCl₃): δ 7.99-7.97 (2H, m), 7.52-7.43 (3H, m) 7.40-7.30 (2H, m),7.23-7.00 (5H, m), 6.87-6.72 (2H, d, J=8 Hz), 4.50-4.10 (3H, m),4.05-3.90 (1H, m), 3.75-3.63 (1H, m), 3.29-3.19 (1H, m), 3.18-3.01 (3H,m), 2.74-2.50 (1H, m), 2.40 (3H, s), 2.26-2.10 (2H, m)

Chiral analytical HPLC (Daicel Chiralcel OD 10 um 4.6×250 mm column):flow rate=1.0 mL/min; isocratic conditions=85:15 A:B, where A=hexanewith 0.1% TFA; B=iPrOH with 0.1% TFA; detector wavelength=220 nm;retention time=17.3 min; ee>90%

EXAMPLE 307

The title compound (14 mg; 64%) was prepared from Example 306 Part Acompound as for Example 306, except that ethyl chlorformate was usedinstead of phenyl chloroformate.

[M+H]⁺=479.2

¹HNMR (CDCl₃): δ 7.99-7.97 (2H, d, J=8 Hz), 7.52-7.45 (3H, m), 7.06 (2H,s), 6.80-6.78 (2H, d, J=8 Hz), 4.21-4.14 (4H, m), 4.01-3.79 (2H, m),3.52-3.47 (1H, t, J=8 Hz), 3.32-2.85 (4H, m), 2.56-2.47 (1H, m), 2.42(3H, s), 2.23-1.89 (2H, m), 1.30-1.27 (3H, t, J=8 Hz)

Chiral analytical HPLC (Daicel Chiralcel AD 10 um 4.6×250 mm column):flow rate=1.0 mL/min; isocratic conditions=90:10 A:B, where A=HEX with0.1% TFA; B=IPA with 0.1% TFA; detector wavelength=220 nm; retentiontime=29.29 min; ee>90%

EXAMPLE 308

Part A compound (48 mg; 90%) was prepared from Example 298 Part Jcompound by the same procedure as the synthesis of Example 302 Part Acompound.

The title compound (26 mg; 86%) was prepared from Part A compound usingthe same procedure as the synthesis of Example 302 from Example 302 PartA compound.

[M+H]⁺=527.1

¹HNMR (CDCl₃): δ 7.98-7.97 (2H, d, J=8 Hz), 7.45-7.29 (5H, m), 7.23-7.02(5H, m), 6.85-6.82 (2H, d, J=8 Hz), 4.45-4.20 (3H, m), 3.84-3.54 (2H,m), 3.13-2.85 (4H, m), 2.62-2.80 (1H, m), 2.37 (3H, s), 2.13-2.03 (2H,m)

Chiral analytical HPLC (Daicel Chiralcel OD 10 um 4.6×250 mm column):flow rate=1.0 mL/min; isocratic conditions=85:15 A:B, where A=HEX with0.1% TFA; B=IPA with 0.1% TFA; detector wavelength=220 nm; retentiontime=21 min; ee>90%

EXAMPLE 309

The title compound (18.4 mg; 67%) was prepared from Example 308 Part Acompound as for Example 302, except that ethyl chlorformate was usedinstead of phenyl chloroformate.

[M+H]⁺=479.2

¹HNMR (CDCl₃): δ 8.00-7.97 (2H, m), 7.50-7.45 (3H, m), 7.05 (2H, s),6.81-6.79 (2H, d, J=8 Hz), 4.21-4.11 (5H, m), 3.65-3.48 (2H, m),3.06-2.86 (4H, m), 2.51-2.69 (1H, m), 2.42 (3H, s), 2.08-1.95 (2H, m),1.29-1.26 (3H, t, J=4 Hz)

Chiral analytical HPLC (Daicel Chiralcel AD 10 um 4.6×250 mm column):flow rate=1.0 mL/min; isocratic conditions=90:10 A:B, where A=HEX with0.1% TFA; B=IPA with 0.1% TFA; detector wavelength=220 nm; retentiontime=29.50 min; ee>90%

EXAMPLE 310

A mixture of tetrahydropyridine-3-carbomethoxyl triflate (0.58 g; 1.3mmol)

(prepared according to the procedure of Astles, P. C., et. al., PCT Int.Appl (2001), WO 0190101), 3-hydroxy-phenylboronic acid (0.24 g; 1.7mmol), (Ph₃P)₄Pd^(o) (0.41 g; 0.35 mmol), and tetrabutylammonium bromide(0.57 g; 1.7 mmol) in dioxane (10 mL) was stirred for 5 h at 90° C. thenwas cooled to RT and concentrated in vacuo. The residue was partitionedbetween EtOAc and brine. The organic layer was dried (MgSO₄) andconcentrated concentrated in vacuo. The residue was chromatographed(SiO₂; 9:1 hexane:EtOAc) to give Part A Compound (0.35 g; 70%).

A mixture of Part A Compound (0.2 g 0.57 mmol), Example 23 Part Acompound (0.19 g; 0.69 mmol) and K₂CO₃ (0.095 g; 0.69 mmol) in MeCN (10mL) was stirred for 8 h at 80° C., then cooled to RT and concentrated invacuo. The residue partitioned between EtOAc and brine. The organiclayer was dried (MgSO₄) and concentrated in vacuo. The residue waschromatographed (SiO₂; 4:1 hex:EtOAc) to give Part B Compound (0.15 g;50%) as an oil.

A solution of Part B Compound (0.1 g; 0.28 mmol) and aqueous KOH (2 mLof a 1 N solution) in MeOH (5 mL) was stirred at RT for 18 h, then wasconcentrated in vacuo. The residue was neutralized with aqueous 1 N HCland extracted with EtOAc (3×). The combined organic extracts were dried(Na₂SO₄) and concentrate in vacuo to give the title compound.

[M+H]⁺=553.2

EXAMPLE 311

A mixture of 3-(3-hydroxyphenyl)-propionic acid methyl ester (3.12 g;17.3 mmol), Example 23 Part A compound (4.86 g; 17.3 mmol)

and K₂CO₃ (4.9 g; 36 mmol) in MeCN (100 mL) was heated overnight at 90°C. in an oil bath. Volatiles were removed in vacuo, and the residue waspartitioned between H₂O and EtOAc. The aqueous phase was extracted withEtOAc (2×) and the combined organic extracts were dried (MgSO₄) andconcentrated in vacuo. The residue was chromatographed (SiO₂; continuousgradient from 100% hex to 100% EtOAc) to give a mixture of the productand unreacted phenol, which was washed repeatedly with aqueous 2N NaOHto furnish purified Part A compound (4.0 g; 63%) as a pale yellow solid.

[M+H]⁺=366.3

To a 0° C. solution of Part A compound (2.02 g; 5.55 mmol) in anhydrousTHF (30 mL) was cautiously added portionwise solid LiAlH₄ (290 mg; 7.63mmol). The reaction was allowed to warm to RT and stirred at RTovernight, then was cautiously quenched with excess aqueous 1 N HCl (30mL). The mixture was extracted with EtOAc (2×). The combined organicextracts were washed with brine, dried (Na₂SO₄) and concentrated invacuo to give Part B compound (1.90 g; 100% crude), which was used inthe next reaction without further purification.

[M+H]⁺=324.4

To a RT suspension of Dess-Martin periodinane (3.6 g; 8.5 mmol) inCH₂Cl₂ (50 mL) was added dropwise a solution of Part B compound (1.90 g;5.64 mmol) in CH₂Cl₂ (10 mL) over 5 min. The reaction was stirred at RTfor 4.5 h, then was concentrated in vacuo. The residue waschromatographed (SiO₂; continuous gradient from 100% hex to 100% EtOAc)to give Part C compound (1.70 g; 90%) as a colorless oil.

Reference: Sano, S.; Yokoyama, K.; Fukushima, M.; Yagi, T.; Nagao, Y.Chem. Commun. 1997, 6, 559-560

To a −78° C. suspension of NaH (65 mg of a 60% mixture; 1.63 mmol) inanhydrous THF (10 mL) under N₂ was added (CF₃CH₂O)₂P(O)CH₂CO₂CH₃ (380μL; 1.79 mmol) dropwise. The solution was stirred at −78° C. for 10 min,after which a solution of Part C compound (343 mg; 1.02 mmol) in THF (5mL) was added dropwise over 5 min. The reaction mixture was stirred for6 h at −78° C. (a significant amount of Part C compound remained at thispoint), then was allowed to warm slowly to RT and stirred overnight atRT. Excess saturated aqueous NH₄Cl was added and the mixture wasextracted with EtOAc (3×). The combined organic extracts were washedwith brine, dried (Na₂SO₄), concentrated in vacuo, and the residue waschromatographed (SiO₂; continuous gradient from 100% hex to 100% EtOAc)to give the Z-isomer Part D compound (199 mg; 50%) as a colorless oil aswell as the E-isomer Part E compound (86 mg; 22%) as a colorless oil.

Part D Compound (Z-Isomer) Data:

¹H NMR (CDCl₃, 400 MHz) δ 2.27 (s, 3H), 2.62 (t. J=7.7 Hz, 2H),2.83-2.90 (m, 4H), 3.58 (s, 3H), 4.14 (t, J=6.6 Hz, 2H), 5.69 (dt,J=11.4, 1.8 Hz, 1H), 6.12 (dt, J=11.4, 7.5 Hz, 1H), 6.6-6.72 (m, 3H),7.08 (t, J=7.9, 1H), 7.28-7.35 (m, 3H), 7.89 (dd, J=7.9, 1.8 Hz, 2H).

Part E Compound (E-Isomer) Data:

¹H NMR (CDCl₃, 400 MHz) δ 2.29 (s, 3H), 2.38-2.46 (m, 2H), 2.64 (t.J=7.9 Hz, 2H), 2.90 (t, J=6.6 Hz, 2H), 3.63 (s, 3H), 4.16 (t, J=6.8 Hz,2H), 5.75 (dt, J=15.8, 1.8 Hz, 1H), 6.6-6.7 (m, 3H), 6.90 (dt, J=15.4,7.0 Hz, 1H), 7.1 (t, J=7.9, 1H), 7.3-7.4 (m, 3H), 7.90 (dd, J=7.9, 1.8Hz, 2H).

To a solution of Part D compound (126 mg; 0.32 mmol) in toluene (4 mL)were successively added Example 1 Part B compound (192 mg; 1.23 mmol)and TFA (4 drops). The reaction was stirred at RT for 2 h, after whichmore Example 1 Part B compound (100 mg) was added. Volatiles wereremoved in vacuo and the residue was chromatographed (SiO₂; continuousgradient from 100% hex to 100% EtOAc) to provide Part F compound (189mg; contains some unreacted Example 1 Part B compound; 100%) as acolorless oil.

A mixture of Part F compound (24 mg; 0.046 mmol) in 20% aqueous HCl(0.25 mL) and HOAc (0.75 mL) was stirred at 80° C. for 3 h, after whichvolatiles were removed in vacuo. The residue was purified by preparativeHPLC (YMC ODS 20×100 mm reverse phase column, 10 min. continuousgradient from 50:50 A:B to 100% B according to the procedure in Example1), then lyophilized from dioxane to provide the title compound (7 mg;25%) as a white solid.

[M+H]⁺=511.6

EXAMPLE 312

To a solution of Example 311 Part E compound (70 mg, 0.179 mmol) intoluene (3 mL) was added Example 1 Part B compound (0.4 g, 1.68 mmol)followed by TFA (2 drops). The mixture was stirred for 16 h at RT,evaporated in vacuo and the residue was chromatographed (SiO₂; 100% hexto 100% EtOAc) to afford Part A compound (34 mg, 36%) as a colorlessoil.

[M+H]⁺=525.5

A solution of Part A compound (34 mg, 0.065 mmol) in 20% HCl:HOAc (1 mLof a 1:3 solution) was heated at 80° C. for 3 h, then cooled to RT andconcentrated in vacuo. The residue was purified by preparative HPLC (YMCODS 20×100 mm reverse phase column, 10 min continuous gradient from70:30 A:B to 100% B, according to the conditions described for thepurification of Example 1) and lyophilized from dioxane to afford thetitle compound (12.8 mg, 32%) as a white solid.

[M+H]⁺=511.6

A mixture of Example 311 Part F compound (5.1 g, 9.7 mmol) in 30%HCOOH—MeOH (50 mL) and Pd black (1 g) was stirred at RT for 16 h. Thecatalyst was filtered off; the filtrate was evaporated in vacuo and theresidue was partitioned between EtOAc and saturated aqueous NaHCO₃. Theaqueous layer was extracted with EtOAc (×2) and the combined organiclayers were washed with brine, dried (Na₂SO₄) and evaporated in vacuo toyield Part A compound (4.3 g; 9.9 mmol; 100%) as a colorless oil.

Part A compound (racemate) was separated into the two individualenantiomers by preparative HPLC (Chiralpak AD chiral column, 5 cm×50 cm,20μ; isocratic 20% EtOH-MeOH (1:1)+85% heptane, flow rate=45 mL/min) toafford Part B compound (1.8 g; faster-eluting enantiomer) and Part Ccompound (2.0 g; slower-eluting enantiomer) as colorless oils. Theabsolute stereochemistry of the two enantiomers is arbitrarily assigned.

A mixture of Part B compound (20 mg, 0.046 mmol),2-chloro-4-trifluoromethylpyrimidine (24 mg, 0.131 mmol) and iPr₂NEt (26μL, 0.15 mmol) in 0.5 mL toluene was stirred at RT for 1 h, then wasconcentrated in vacuo. The residue was purified by preparative HPLC (YMCODS 20×100 mm reverse phase column, 10 min continuous gradient from20:80 A:B to 100% B according to the procedure in Example 1) to yieldPart D compound (22 mg; 82%) as a colorless oil. The absolutestereochemistry of Part D compound is arbitrarily assigned.

[M+H]⁺=581.4

A solution of Part D compound (22 mg, 0.038 mmol) in 20% HCl:HOAc (1:3;1 mL) was heated at 70° C. for 19 h, then was concentrated in vacuo. Theresidue was purified by preparative HPLC (Phenomenex LUNA 5μ C18(2)21.2×100 mm reverse phase column, 10 min. continuous gradient from 20:80A:B to 100% B as described in the general procedure in Example 1) toafford the title compound (13.5 mg, 63%) as a colorless oil.

[M+H]⁺=567.4

EXAMPLE 314

The title compound (racemate) was prepared according to the sequencedescribed for the synthesis of Example 318 using phenyl chloroformateand Example 313 Part A compound (racemate).

[M+H]⁺=541.5

EXAMPLE 315

The title compound (racemate) was prepared using ethyl chloroformate andExample 313 Part A compound (racemic) according to the sequencedescribed for the synthesis of Example 318.

[M+H]⁺=493.5

EXAMPLE 316

The title compound was prepared in the same way as for Example 315, butusing Example 313 Part B compound (chiral).

[M+H]⁺=493.3

EXAMPLE 317

The title compound was synthesized in the same way as Example 316, butfrom Example 313 Part C compound and ethyl chloroformate.

[M+H]⁺=493.3

EXAMPLE 318

To a solution of Example 313 Part B compound (120 mg, 0.286 mmol) inCH₂Cl₂ (5 mL) was added Et₃N (80 μL, 0.575 mmol) followed by phenylchloroformate (50 μL, 0.4 mmol) at RT. The reaction mixture was stirredfor 3 h at RT, then was partitioned between CH₂Cl₂ (25 mL) and 1Naqueous HCl (20 mL). The organic phase was washed with brine, dried(Na₂SO₄) and concentrated in vacuo. The residue was chromatographed(SiO₂, continuous gradient from 100% hex to 100% EtOAc) to afford Part Acompound (144 mg, 91%) as a colorless oil.

A solution of Part A compound (144 mg, 0.26 mmol) in 20% HCl:HOAc (3 mLof a 1:3 solution) was heated at 70° C. for 19 h, then was cooled to RTand concentrated in vacuo. The residue was purified by preparative HPLC(YMC ODS 20×100 mm reverse phase column, 10 min continuous gradient from20:80 A:B to 100% B according to the general procedure for Example 1)afforded the title compound (135 mg, 96%) as a pale yellow solid. Theabsolute stereochemistry is arbitrarily assigned.

[M+H]⁺=541.38

EXAMPLE 319

The title compound was prepared in the same manner as for the synthesisof Example 318 using Example 313 Part C compound and phenylchloroformate. The absolute stereochemistry is arbitrarily assigned.

EXAMPLES 320-330

Examples 320-330 of the invention were prepared as part of a libraryusing the same sequence for the preparation of Example 318 starting fromracemic cis Example 313 Part A compound and an appropriatechloroformate.

Example Number R [M + H]⁺ 320

507.6 321

507.6 322

521.6 323

521.6 324

535.6 325

555.6 326

559.6 327

575.5 328

619.5 329

555.6 330

571.6

EXAMPLE 331

A mixture of Example 312 Part A compound (240 mg, 0.46 mmol) and Pdblack (235 mg) in 30% HCOOH—MeOH (5 mL) was stirred at RT for 3.5 h. Thecatalyst was filtered off; the filtrate was concentrated in vacuo andpartitioned between EtOAc and saturated aqueous NaHCO₃. The aqueouslayer was extracted with EtOAc (×2) and the combined organic layers werewashed with brine, dried (Na₂SO₄) and evaporated in vacuo to yield crudePart A compound (220 mg; 100%, purity 92%) as a colorless oil.

Crude Part A compound (24 mg, 0.05 mmol) was reacted with isopropylchloroformate (60 μL; 0.06 mmol), Et₃N (40 μL, 0.287 mmol) in CH₂Cl₂ (2mL) as in Example 318 Part A compound to give Part B compound as an oilwhich was used in the next step without further purification.

Part B compound was hydrolyzed to the acid using the same procedure asfor Example 318 Part B to give the title compound (3.6 mg; 14% for 3steps) as a colorless solid.

EXAMPLES 332-339

Examples 332-339 of the invention were prepared as part of a library inusing the same sequence as for the synthesis of Example 331 (fromExample 331 Part A compound and appropriate chloroformates).

Example Number R [M + H]⁺ 332

521.7 333

521.6 334

535.7 335

559.6 336

575.6 337

619.6 338

555.6 339

571.6

EXAMPLE 340

A mixture of 4-hydroxyphenylpropanoic acid ethyl ester (1.8 g; 9.28mmol), Example 23 Part A compound (2.63 g; 9.36 mmol)

and K₂CO₃ (2.65 g; 19.2 mmol) in MeCN (50 mL) was heated overnight at90° C. in an oil bath. Volatiles were removed in vacuo and the residuewas partitioned between H₂O and EtOAc. The aqueous phase was extractedwith EtOAc (2×) and the combined organic extracts were dried (MgSO₄) andconcentrated in vacuo. The residue was chromatographed (SiO₂; continuousgradient from 100% hex to 100% EtOAc) to give part A compound (1.9 g,54%) as a white solid.

[M+H]⁺=380.3

To a 0° C. solution of Part A compound (1.87 g; 5 mmol) in anhydrous THF(30 mL) was cautiously added portionwise solid LiAlH₄ (295 mg; 7.6mmol). The reaction mixture was allowed to warm to RT, stirred at RTovernight, then was cautiously quenched with excess aqueous 1 N HCl. Themixture was extracted with EtOAc (2×). The combined organic extractswere washed with brine, dried (Na₂SO₄) and concentrated in vacuo. Theresidue was chromatographed (SiO₂; continuous gradient from 100% hex to100% EtOAc) to give crude Part B compound (1.49 g; 88%) as a golden oil.

To a RT suspension of Dess-Martin periodinane (2.1 g; 4.95 mmol) inCH₂Cl₂ (30 mL) was added dropwise a solution of Part B compound (1.49 g;4.42 mmol) in CH₂Cl₂ (30 mL) over 5 min. The reaction was stirred at RTfor 1 h, then was concentrated in vacuo. The residue was chromatographed(SiO₂; continuous gradient from 100% hex to 100% EtOAc) to give Part Ccompound (1.41 g; 95%) as a colorless solid.

To a −78° C. suspension of NaH (340 mg of a 60% mixture; 8.5 mmol) inanhydrous THF (40 mL) under N₂ was added (CF₃CH₂O)₂P(O)CH₂CO₂CH₃ (2.2mL; 10.41 mmol) dropwise. The solution was stirred at −78° C. for 10min, after which a solution of Part C compound (1.41 g; 4.21 mmol) inTHF (10 mL) was added dropwise over 5 min. The reaction mixture was thenallowed to warm slowly to RT and stirred overnight at RT. Excesssaturated aqueous NH₄Cl was added and the mixture was extracted withEtOAc (3×). The combined organic extracts were washed with brine, dried(Na₂SO₄), concentrated in vacuo, and the residue was chromatographed(SiO₂; continuous gradient from 100% hex to 100% EtOAc) to give theZ-isomer Part D compound (1.16 g; 70.2%) as a colorless oil as well asthe E-isomer Part E compound (209 mg; 12.7%) as a colorless solid.

LC-MS for Part D: [M+H]⁺=392.3;

TLC: R_(f) (7:3 hex:EtOAc)=0.43 (Part D compound, Z-isomer).

TLC: R_(f) (7:3 hex:EtOAc)=0.36 (Part E compound, E-isomer)

To a solution of Part D compound (1.04 g, 2.66 mmol) in toluene (10 mL)was added Example 1 Part B compound (1.0 gm, 4.2 mmol) followed by TFA(5 drops). The mixture was stirred for 16 h at RT, concentrated in vacuoand the residue was chromatographed (SiO₂; continuous gradient from 100%hex to 100% EtOAc) to afford Part F compound (1.26 g, 91%) as acolorless oil.

[M+H]⁺=525.4

Part G compound (trans isomer) was prepared (in a similar manner to PartF compound) from Part E compound (E-alkene) in quantitative yield.

A solution of Part F compound (11.8 mg, 0.023 mmol) in 20% HCl:HOAc (1mL of a 1:3 solution) was heated at 75° C. for 3.5 h, then was cooled toRT and concentrated in vacuo. The residue was purified by preparativeHPLC (Phenomenex LUNA 5μ C18(2) 21.2×100 mm reverse phase column, 10 mincontinuous gradient from 30:70 A:B to 100% B according to the generalprocedure of Example 1) to afford the title compound (10.7 mg, 93%) as acolorless oil. [M+H]⁺=511.4

EXAMPLE 341

The title compound was prepared from the E-alkenyl ester Example 340Part G compound (using the same procedure as for the synthesis ofExample 340).

[M+H]⁺=511.4

EXAMPLE 342

A mixture of Example 340 Part F compound (1.24 g, 2.36 mmol) and Pdblack (164 mg) in 30% HCOOH—MeOH (12 mL) was stirred at RT for 16 h. Thecatalyst was filtered off; the filtrate was concentrated in vacuo, thenpartitioned between EtOAc and saturated aqueous NaHCO₃. The aqueouslayer was extracted with EtOAc (×2) and the combined organic layers werewashed with brine, dried (Na₂SO₄) and concentrated in vacuo to yieldPart A compound (983 mg; 2.26 mmol, 96%) as a colorless oil.

[M+H]⁺=435.4

To a solution of Part A compound (20 mg, 0.11 mmol) in CH₂Cl₂ (0.5 mL)was added Et₃N (25 μL, 0.18 mmol) and ethyl chloroformate (20 μL, 0.21mmol) and the mixture was stirred at RT for 2 h. Volatiles were removedin vacuo and the residue was purified by preparative HPLC (PhenomenexLUNA 5μ C18(2) 21.2×100 mm reverse phase column, 10 min continuousgradient from 20:80 A:B to 100% B according to the general procedure inExample 1).

[M+H]⁺=507.3

A solution of Part B compound in 20% HCl:HOAc (1 mL of a 1:3 solution)was heated at 75° C. overnight, then was cooled to RT and concentratedin vacuo. The residue was purified by preparative HPLC (YMC ODS 20×100mm reverse phase column, 10 min continuous gradient from 20:80 A:B to100% B according to the procedure in Example 1) afforded the titlecompound (14.6 mg; 64% for 2 steps).

[M+H]⁺=493.5

EXAMPLES 343-345

Examples 343-345 of the invention were prepared according to the generalprocedure described for the synthesis of Example 342 (using Example 342Part A compound and appropriate chloroformates).

Example Number R [M + H]⁺ 343

521.5 344

541.5 345

559.5

EXAMPLE 346

Part A compound was obtained by Pd black-catalyzed hydrogenolysis ofExample 340 Part G compound following a procedure similar to Example 342Part A.

The title compound was prepared from Part A compound according to theprocedure described in Example 342.

[M+H]⁺=493.4

EXAMPLE 347

The title compound was obtained in a similar manner as for Example 346from Example 346 Part A compound using ethyl chlorformate.

[M+H]⁺=541.4

EXAMPLE 348 Enantiomer 1

The two enantiomers of racemic Example 342 Part A compound (800 mg) wereseparated by preparative HPLC: Chiralpak AD chiral column; 5 cm×50 cm,20μ; isocratic 15% EtOH-MeOH (1:1)+85% heptane+0.1% Et₂NH) to affordPart A compound (284 mg; faster-eluting enantiomer) and Part B compound(232 mg; slower-eluting enantiomer) as well as 71 mg of mixed fractionsas colorless oils. The absolute stereochemistry of the two enantiomersis arbitrarily assigned.

Example 348 was prepared according to the procedure in Example 342 fromethyl chloroformate and Part A compound.

[M+H]⁺=493.3

EXAMPLE 349 Enantiomer 2

The title compound was prepared according to the procedure in Example342 from ethyl chloroformate and Part B compound.

[M+H]⁺=493.3

EXAMPLE 350

A solution of Example 342 Part A compound (20 mg, 0.046 mmol),2-chloro-4-trifluoromethylpyrimidine (30 mg, 0.166 mmol) and iPr₂NEt (26μL, 0.15 mmol) in CH₂Cl₂ (0.5 mL) were stirred at RT overnight, then wasconcentrated in vacuo. The residue was purified by preparative HPLC(Phenomenex LUNA 5μ C18(2) 21.2×100 mm reverse phase column, 10 mincontinuous gradient from 20:80 A:B to 100% B according to the generalprocedure described in Example 1) to yield Part A compound as acolorless oil which was used in the next step without furtherpurification.

[M+H]⁺=581.4

A solution of Part A compound in 20% HCl:HOAc (1 mL of a 1:3 solution)was heated at 75° C. for 19 h, then was cooled to RT and concentrated invacuo. The residue was purified by preparative HPLC (YMC ODS 20×100 mmreverse phase column, 10 min continuous gradient from 20:80 A:B to 100%B according to the procedure described in Example 1) to afford the titlecompound (5.2 mg, 20% for 2 steps) as a colorless oil.

[M+H]⁺=567.4

EXAMPLE 351

The title compound was prepared in a similar manner as for the synthesisof Example 350 using Example 174 Part A compound.

[M+H]⁺=513.5

EXAMPLE 352

A mixture of 3-(3-hydroxyphenyl)-propionic acid methyl ester (3.2 g,17.83 mmol), K₂CO₃ (4.9 g, 35.5 mmol), Example 89 Part B compound (3.72g, 17.93 mmol) in CH₃CN (50 mL) was heated at 80° C. for 16 h, then wascooled to RT and filtered. The filtrate was concentrated in vacuo andpartitioned between EtOAc and H₂O. The aqueous layer was extracted withEtOAc (×2) and the combined organic layers were washed with brine, dried(Na₂SO₄), filtered and evaporated in vacuo. The residue waschromatographed (SiO₂; continuous gradient from 100% hex to 100% EtOAc)to afford Part A compound (4.26 g, 68%) as a golden oil.

[M+H]⁺=352.3

To a 0° solution of Part B compound (4.3 g, 12.1 mmol) in THF (50 mL)was added LiAlH₄ (600 mg, 15.8 mmol) and the reaction was allowed towarm to RT and stirred at RT for 16 h. The mixture was then quenchedcautiously with 1N aqueous HCl, extracted with EtOAc (×2), washed withbrine, dried (Na₂SO₄) and evaporated in vacuo. The residue waschromatographed (SiO₂; continuous gradient 100% hex to 100% EtOAc) toafford Part B compound (3.3 gm, 84%) as a colorless solid.

[M+H]⁺=324.4

To a dispersion of Dess-Martin reagent (5.0 g, 11.8 mmol) in CH₂Cl₂ (25mL) was added a solution of Part B compound (3.3 g, 10.2 mmol) in CH₂Cl₂(35 mL) dropwise at RT and the resulting mixture was allowed to stir atRT for 1 h. The mixture was then evaporated in vacuo and the residue waschromatographed (SiO₂; 100% hex to 100% EtOAc) to yield Part C compound(2.69 g, 82%) as a golden oil.

A suspension of NaH (60% dispersion in oil, 670 mg, 16.75 mmol) in THF(100 mL) was stirred at RT for 15 min and then cooled to −78° C.[Bis-(2,2,2-trifluoro-ethoxy)-phosphoryl]-acetic acid methyl ester (4.5mL, 21.3 mmol) was added and the mixture was stirred for 20 min at −78°C. A solution of Part C compound (2.69 gm, 8.38 mmol) in THF (20 mL) wasthen added dropwise to the −78° C. reaction. The reaction was allowed towarm to RT and stirred at RT for 16 h, then was quenched with aqueousNH₄Cl. The aqueous phase was extracted with EtOAc (×2); the combinedorganic layers were washed with brine, dried (Na₂SO₄) and evaporated invacuo. The residue was chromatographed (SiO₂; continuous gradient from100% hex to 100% EtOAc; 3 times) to afford Part D compound (Z-alkene;2.22 g, 70%) and Part E compound (E-alkene; 0.346 g, 11%).

To a solution of Part D compound (2.22 g, 5.88 mmol) in toluene (20 mL)was added Example 1 Part B compound (2.14 gm, 9 mmol) followed by TFA (5drops). The mixture was stirred for 16 h at RT, evaporated in vacuo andthe residue was chromatographed (SiO₂; 100% hex to 100% EtOAc) to affordPart F compound (3.0 g, 100%) as a colorless oil.

[M+H]⁺=511.6

A solution of Part F compound (51 mg, 0.1 mmol) in 20% HCl:HOAc (3 mL ofa 1:3 solution) was heated at 70° C. for 5 h, then was cooled to RT andconcentrated in vacuo. The residue was purified by preparative HPLC (YMCODS 20×100 mm reverse phase column, 10 min continuous gradient from70:30 A:B to 100% B according to the general procedure in Example 1) toafford the title compound (0.8 mg, 1.6%) as a colorless oil.

[M+H]⁺=497.4

EXAMPLE 353

To a solution of Example 352 Part E compound (346 mg, 0.92 mmol) intoluene (5 mL) was added Example 1 Part B compound (387 mg, 1.63 mmol)followed by TFA (5 drops). The mixture was stirred for 16 h at RT,evaporated in vacuo and the residue was chromatographed (SiO₂; 100% hexto 100% EtOAc) to afford Part A compound (414 mg, 88%) as a colorlessoil.

[M+H]⁺=511.6

A solution of Part A compound (16 mg, 0.03 mmol) in 20% HCl:HOAc (2 mLof a 1:3 solution) was heated at 70° C. for 5 h, then was cooled to RTand concentrated in vacuo. The residue was purified by preparative HPLC(YMC ODS 20×100 mm reverse phase column, 10 min continuous gradient from70:30 A:B to 100% B according to the general procedure in Example 1) toafford the title compound (1.5 mg, 10%) as a colorless oil.

[M+H]⁺=497.4

EXAMPLE 354

A mixture of Example 352 Part F compound (514 mg, 1 mmol) and Pd black(392 mg) in 30% HCO₂H-MeOH (5 mL) was stirred at RT for 16 h. Thereaction mixture was filtered, evaporated in vacuo and partitionedbetween EtOAc and saturated aqueous NaHCO₃. The aqueous layer wasextracted with EtOAc (×2) and the combined organic layers were washedwith brine, dried (Na₂SO₄) and concentrated in vacuo to yield crude PartA compound (369 mg; 0.88 mmol, 88%) as a colorless oil.

[M+H]⁺=421.3

To a solution of Part A compound (44 mg, 0.11 mmol) in CH₂Cl₂ (2 mL) wasadded Et₃N (50 μL, 0.36 mmol) and isobutyl chloroformate (35 μL, 0.27mmol) and the mixture was stirred at RT for 1 h. The mixture was thenevaporated in vacuo and purified by preparative HPLC (YMC ODS 20×100 mmreverse phase column, 10 min continuous gradient from 20:80 A:B to 100%B according to the general procedure described in Example 1) to givePart A compound.

[M+H]⁺=521.5

A solution of Part B compound in 20% HCl:HOAc (1 mL of a 1:3 solution)was heated at 70° C. for 3 h, then was cooled to RT and concentrated invacuo. The residue was purified by preparative HPLC (YMC ODS 20×100 mmreverse phase column, 10 min continuous gradient from 30:70 A:B to 100%B according to the general procedure described in Example 1) to affordthe title compound (3.3 mg; 6% for 2 steps) as a colorless oil.

[M+H]⁺=507.5

EXAMPLES 355-357

Examples 355-357 of the invention (cis-disubstituted pyrrolidinecompounds) were prepared in the same manner as for Example 356:

Example Number R [M + H]⁺ 355

479.5 356

527.5 357

545.5

EXAMPLE 358

A mixture of Example 353 Part A compound (395 mg, 0.78 mmol) in 30%HCOOH—MeOH (5 mL) and Pd black (318 mg) was stirred at RT under for 16h. The reaction mixture was filtered; the filtrate was concentrated invacuo and partitioned between EtOAc and saturated aqueous NaHCO₃. Theaqueous layer was extracted with EtOAc (×2) and the combined organiclayers were washed with brine, dried (Na₂SO₄) and concentrated in vacuoto give crude Part A compound (294 mg; 0.7 mmol, 90%) as a golden oil.

[M+H]⁺=421.3

The title compound was prepared from Part A compound in the same manneras for the synthesis of Example 354 in 5% yield for 2 steps.

[M+H]⁺=479.1

EXAMPLES 359-361

The following compounds of the invention were prepared according to thesame procedure as Example 354 starting from Example 358 Part A compound.

Example Number R [M + H]⁺ 361

507.1 362

527.1 363

545.1

EXAMPLE 362

To a 0° C. solution of ethyl 1-benzyl-3-oxo-4-piperidine carboxylatehydrochloride (5.0 g, 16.77 mmol) in MeOH (16 mL) was added aqueousK₂CO₃ (2.55 g, 18.47 mmol; in 26 mL H₂O). The mixture was stirred at 0°C. for 10 min, then was extracted with CH₂Cl₂ (4×30 mL). The combinedorganic extracts were dried (K₂CO₃) and concentrated in vacuo to givethe corresponding free base (3.5 g, 80%). The β-keto ester free base(1.37 g, 5.22 mmol) was stripped from toluene (2×), dissolved inanhydrous THF (50 mL) and cooled to −70° C. under Ar. KN(TMS)₂ intoluene (13.5 mL of a 0.5 M solution) was added dropwise. After stirringat −70° C. for 15 min, 1,1,2,2,3,3,4,4,4-Nonafluoro-1-butanesulfonylfluoride (1.28 mL, 6.78 mmol) was added. The reaction was allowed towarm to RT and stirred overnight at RT, then was washed with saturatedaqueous NH₄Cl (200 mL). The aqueous layer was extracted with Et₂O (3×50mL). The combined organic extracts were dried (Na₂SO₄) and concentratedin vacuo to give Part A compound as a brown oil (2.84 g, 100%), whichwas used in the next step without further purification.

[M+H]⁺=544.4

¹H NMR (400 MHz, CDCl₃) δ 7.26 (m, 5H), 4.21 (q, J=7.0 Hz, 2H), 3.59 (s,2H), 3.12 (s, 2H), 2.58 (m, 2H), 2.52 (m, 2H), 1.24 (t, J=7.0 Hz, 3H)

To a solution of Bis(dibenzylideneacetone)palladium (0) [Pd(dba)₂] (0.18g, 0.31 mmol) and 1,1′-Bis(diphenyl-phosphino)ferrocene (dppf) (0.18 g,0.31 mmol) in anhydrous THF (21 mL) under Ar was added 4-methoxybenzylzinc chloride (25.0 ml, 11.5 mmol, 0.5 M in THF) at RT. The reagentmixture was stirred at RT for 20 min. A solution of Part A Compound(2.84 g, 5.22 mmol; stripped from anhydrous toluene 3× before use) indry THF (20 mL) was added slowly to the Pd catalyst/organozinc reagentmixture. The mixture was heated at 65° C. under Ar for 12 h, cooled toRT, and partitioned between CH₂Cl₂ (70 mL) and saturated aqueous NaHCO₃.Solids were filtered off, and the aqueous phase was extracted withCH₂Cl₂ (4×30 mL). The combined organic extracts were dried (K₂CO₃) andconcentrated in vacuo. The residue was chromatographed (SiO₂; 85:15hexane:EtOAc) to afford Part B compound as a light yellow oil (1.37 g,72%).

[M+H]⁺=366.5

To a 0° C. solution of compound B (1.0 g, 2.74 mmol) in CH₂Cl₂ (15 mL)was added dropwise BBr₃ in CH₂Cl₂ (6.5 mL of a 1.0 M solution; 6.49mmol). The mixture was stirred at 0° C. for 2 h. EtOH (1 mL) andsaturated aqueous NaHCO₃ (10 mL) were subsequently added to quench thereaction. The aqueous phase was further extracted with CH₂Cl₂ (3×10 mL).The combined organic extracts were dried (Na₂SO₄) and concentrated invacuo. The residue was chromatographed (SiO₂; 4:1 hex:EtOAc) to affordPart C compound (0.59 g, 61%) as light yellow solid.

Part C compound (0.264 g, 0.753 mmol) and Example 23 Part A compound(0.265 g, 0.942 mmol) were stripped from dry toluene (3×), then weredissolved in anhydrous MeCN (7.5 mL); finally anhydrous K₂CO₃ (0.13 g,0.942 mmol) was added. The reaction was stirred at 90° C. overnight.Additional Example 23 Part A compound was added until all Part Ccompound was consumed. Volatiles were removed in vacuo and the residuewas dissolved in water (15 mL) and extracted with CH₂Cl₂ (3×15 mL). Thecombined organic extracts were dried (K₂CO₃) and concentrated in vacuo.The residue was chromatographed (SiO₂; 4:1 hex:EtOAc) to give compound D(0.202 g, 50%) as a light yellow oil.

A solution of Part D compound in HCl/HOAc (1 mL of a conc. HCl:HOAcsolution; 20:80 v/v) was heated at 90° C. in a sealed tube for 8 h, thencooled to RT. Volatiles were removed in vacuo, and the residue waspurified by preparative HPLC (YMC S5 ODS 20×250 mm column; continuousgradient from 50:50 solvent A:B to 100% solvent B; where solventA=90:10:0.1H₂O:CH₃CN:TFA; solvent B=90:10:0.1 CH₃CN:H₂O:TFA) andlyophilized from CH₃CN/H₂O to give the title compound (5.6 mg, 50%) asthe TFA salt (light yellow oil).

[M+H]⁺ (electrospray)=509.0

EXAMPLE 363

Example 362 Part D Compound (40 mg, 0.0745 mmol) and Proton Sponge[1,8-bis(dimethylamino)naphthalene] (2.0 mg) were stripped from drytoluene (2×), then dissolved in CH₂Cl₂ (1 mL). To this 0° C. solutionwas added dropwise α-chloroethyl chloroformate (21 μL, 0.186 mmol). Thereaction mixture was allowed to warm to RT, then heated at 40° C. underAr for 1 h. Volatiles were removed in vacuo; MeOH (1 mL) was added, andthe mixture was heated at 50° C. for 1 h, then cooled to RT. Volatileswere removed in vacuo to afford crude Part A compound as a light yellowoil, which was used in the next reaction without further purification.

[M+H]⁺=447.5

To a solution of Part A compound (ca 0.0745 mmol) in 1,4-dioxane/H₂O(2.0 mL of a 1:1 solution) were successively added isobutylchloroformate (15.0 μL, 0.064 mmol) and NaHCO₃ (25.0 mg, 0.298 mmol).The mixture was stirred at RT for 1 h, then was partitioned betweenwater (3 mL) and CH₂Cl₂ (5 mL). The aqueous phase was extracted withCH₂Cl₂ (2×5 mL). The combined organic extracts were dried (Na₂SO₄) andconcentrated in vacuo. The residue was chromatographed (SiO₂; 3:1hex:EtOAc) to give Part B compound as a colorless oil (32.5 mg, 80%).

[M+H]⁺=547.2

A solution of Part B Compound (32.5 mg, 0.0595 mmol) in 20% HCl/HOAc(2.0 mL of a conc HCl:HOAc solution; 20:80 v/v) was heated at 110° C. ina sealed tube for 2 h, then cooled to RT. Volatiles were removed invacuo, and the residue was purified by preparative HPLC (YMC S5 ODS 20mm×100 mm column; continuous gradient from 70% A:30% B to 100% B for 10min; flow rate=20 mL/min, where A=90:10:0.1H₂O:MeOH:TFA and whereB=90:10:0.1 MeOH:H₂O:TFA) to give the title compound (15.4 mg; 50%) as acolorless solid.

[M+H]⁺=519.0

EXAMPLE 364

A mixture of Example 362 Part D Compound (0.26 g, 0.48 mmol) and 10%Pd/C (0.1 g) in HOAc (4.8 mL) was stirred overnight under an atmosphereof H₂ (60 psi pressure). The catalyst was filtered off, and the filtratewas concentrated in vacuo to afford crude Part A compound as a lightyellow oil (0.117 g, 54%), which was used in the next step withoutfurther purification.

[M+H]⁺=449.5

A mixture of Part A Compound (38.5 mg, 0.086 mmol),2-Chloro-4-(trifluoromethyl)pyrimidine (21 μL, 0.172 mmol) and iPr₂NEt(40 μL, 0.215 mmol) in dry toluene (1 mL) was heated at 100° C. for 3 h.Volatiles were removed in vacuo, and the residue was purified bypreparative HPLC (YMC S5 ODS 20 mm×100 mm column; continuous gradientfrom 70% A:30% B to 100% B for 10 min; flow rate=20 mL/min, whereA=90:10:0.1H₂O:MeOH:TFA and where B=90:10:0.1 MeOH:H₂O:TFA) to give PartB compound (22.2 mg, 44% yield) as a white solid.

[M+H]⁺=595.6

Part B Compound (22.2 mg, 0.0373 mmol) was: 1) deprotected using thestandard HCl/HOAc/110° C. procedure and 2) purified by preparative HPLC,both as for Example 363 Part C. The title compound was obtained as awhite solid (12.6 mg, 60%).

[M+H]⁺=567.0

EXAMPLE 365

To a solution of Example 364 Part A compound (35.5 mg, 0.0793 mmol) in1,4-dioxane/H₂O (2.0 mL of a 1:1 solution) were added isobutylchloroformate (15.0 μL, 0.111 mmol) and NaHCO₃ (27.0 mg, 0.317 mmol).The mixture was stirred at RT for 1 h, then water (3 mL) was added. Theaqueous phase was extracted with CH₂Cl₂ (3×5 mL). The combined organicextracts were dried (Na₂SO₄) and concentrated in vacuo to give crudePart A compound.

Crude Part A Compound was: 1) deprotected using the same HCl/HOAc/110°C. procedure and 2) purified by preparative HPLC both as for Example 363Part C. The title compound was obtained as a white solid (20.6 mg, 50%yield). [M+H]⁺=521.1

EXAMPLE 366

Example 364 Part A compound (20 mg, 0.045 mmol) was reacted with phenylchloroformate (8.5 μL, 0.067 mmol), followed by the acid-mediatedhydrolysis of the ester (both steps as for Example 365) to give thetitle compound (12.0 mg, 50% yield) as a white solid.

[M+H]⁺=541.0

EXAMPLE 367

Example 363 Part A compound (76.7 mg; 0.171 mmol) was reacted with2-chloro-4-(trifluoromethyl)pyrimidine (41.7 μL; 0.342 mmol), followedby acid-mediated hydrolysis (both steps following the general proceduresdescribed in Example 365) to give the title compound (29 mg; 30%) aswhite solid.

[M+H]⁺=565.0

EXAMPLE 369

3-methoxybenzylzinc chloride (15 mL of a 0.5 M solution in THF, 7.47mmol) was reacted with Example 362 Part A compound (1.85 g, 3.40 mmol)according the general procedure described for the preparation of Example362 Part B compound to give Part A compound (0.972 g, 78%) as a lightyellow oil.

[M+H]⁺=366.5

¹H NMR (400 MHz, CDCl₃) δ 7.24-6.69 (m, 6H), 6.66-6.63 (m, 3H), 4.10 (q,J=7.1 Hz, 2H), 3.69 (s, 3H), 3.68 (s, 2H), 3.41 (s, 2H), 2.90 (s, 2H),2.46-2.40 (m, 4H), 1.16 (t, J=7.1 Hz, 3H)

¹³C NMR (400 MHz, CDCl₃) δ 167.6, 159.5, 145.0, 140.7, 137.7, 129.1,128.8, 128.1, 127.0, 124.1, 121.0, 114.3, 111.3, 61.7, 60.1, 56.8, 55.0,48.9, 38.1, 26.9, 14.1

Part A Compound was subjected to BBr₃ deprotection using the generalprocedure described for Example 362 Part C compound. Part B compound(42%) was isolated as a brown oil.

[M+H]⁺=352.4

Part C compound was prepared from Part B compound as a light yellow oil(50%) following the general procedure described for the synthesis ofExample 362 Part D compound.

[M+H]⁺=537.7

The title compound was obtained from Part C compound following thegeneral procedure described in Example 362 Part E compound. The titlecompound (50%) was obtained as a brown solid.

[M+H]⁺=509.0

EXAMPLE 370

A mixture of Example 369 Part A compound (0.824 g, 2.25 mmol) and 10%Pd—C (1.65 g) in HOAc (23 mL) was stirred overnight under an atmosphereof H₂ (80 psi pressure). The catalyst was filtered off and volatileswere removed in vacuo to give Part A compound as a brown oil, which wasused in the next step without further purification.

To a 0° C. solution of crude Part A compound in CH₂Cl₂ (23 mL) was addedBBr₃ (11.7 mL, 11.7 mmol, 1 M in CH₂Cl₂ added slowly over 15 min. Thereaction was stirred at 0° C. for 1 h, then was quenched with MeOH (1mL) and saturated aqueous NaHCO₃ (10 mL). The organic layer wasseparated; the aqueous layer was extracted with CH₂Cl₂ (3×15 mL). Thecombined organic extracts were concentrated in vacuo to give crude PartB compound as a brown oil.

To a solution of Part B compound in 1,4-dioxane-H₂O (20 mL, 1:1 v/v) wasadded di-tert-butyl dicarbonate (0.419 g, 1.91 mmol) and NaHCO₃ (0.322g, 3.83 mmol) The mixture was stirred at RT for 1 h, then waspartitioned between H₂O and EtOAc (15 mL each). The aqueous layer wasextracted with EtOAc (2×15 mL) and the combined organic extracts weredried (Na₂SO₄), and concentrated in vacuo. The residue waschromatographed (SiO₂; stepwise gradient from 4:1 to 65:35 hex:EtOAc) togive the title compound as a colorless oil (0.413 g, 51% yield over 3steps).

[M+H]⁺=364.4

¹H NMR (400 MHz, CDCl₃) δ 7.05 (t, J=7.5 Hz, 1H), 6.65-6.61 (m, 3H),4.11 (m, 2H), 3.92 (m, 1H), 3.78 (m, 1H), 2.90-2.86 (m, 2H), 2.60-2.17(m, 4H), 1.75 (m, 2H), 1.38 (s, 9H), 1.23 (t, 7.1 Hz, 3H)

Part C compound (0.413 g, 1.13 mmol) and2-(5-methyl-2-phenyloxazole-4-yl)ethanol (0.255 g, 1.25 mmol) werestripped from dry toluene (3×). To a mixture of these two compounds indry toluene (12 mL) was added Bu₃PCHCN (0.302 g, 1.25 mmol). The mixturewas heated at 50° C. under Ar for 2 h, cooled to RT and volatiles wereremoved in vacuo. The residue was chromatographed (SiO₂; 5:1 to 7:3hex:EtOAc) to give Part D compound as a colorless oil (0.370 g, 60%).

To a 0° C. solution of MeOH (4.0 mL) was slowly added acetyl chloride(1.2 mL). The mixture was stirred at 0° C. for 1 h, then was added toPart D compound (50 mg, 0.091 mmol). The mixture was stirred at 0° C.for 15 min and then was allowed to warm to RT. Volatiles were removed invacuo to give crude Part E compound (41.1 mg, 93%), which was used inthe next reaction without further purification. [M+H]⁺=449.5

Part E compound was reacted with 2-chloro-4-(trifluoromethyl)pyrimidineusing the procedure described in Example 364. The crude product fromthis reaction was subjected to acid-mediated hydrolysis and preparativeHPLC (as for Example 363) to afford the title compound as a white solid(27% for 2 steps). [M+H]⁺=567.4

EXAMPLE 371

Example 370 Part E compound was reacted with iso-butyl chloroformatefollowed by acid-mediated hydrolysis and preparative HPLC purification(as described for Example 363) to afford the title compound as a whitesolid.

[M+H]⁺=521.3

EXAMPLE 372

Example 370 Part E compound was reacted with 2-chloro-4-methylpyrimidine(Example 174 Part A compound) according to the general proceduredescribed in Example 364 Part B compound. The crude product wassubjected to acid hydrolysis and HPLC purification (as for Example 363)to afford the title compound as a white solid (30% yield for two steps).[M+H]⁺=513.4

EXAMPLE 373

A mixture of 3-hydroxybenzaldehyde (3.59 g, 28.51 mmol),t-butyldimethylsilyl chloride (5.1 g, 32.79 mmol) and imidazole (3.92 g,57.02 mmol) in DMF (50 mL) was stirred at RT for 2 h, then waspartitioned between saturated aqueous NH₄Cl (100 mL) and Et₂O (50 mL).The aqueous phase was extracted with Et₂O (2×50 mL); the combinedorganic extracts were washed with H₂O (2×50 mL), brine (50 mL), dried(Na₂SO₄), and concentrated in vacuo to afford Part A Compound as ayellow oil (6.74 g, 100% yield).

To a 0° C. solution of Part A compound (6.74 g; 28.5 mmol) in MeOH (100mL) was added NaBH₄ (2.37 g, 62.7 mmol) portionwise over 10 min, and thereaction was stirred at 0° C. for 1 h. Saturated aqueous NH₄Cl (100 mL)was added, and the mixture was extracted with EtOAc (3×50 mL). Thecombined organic extracts were washed with H₂O (2×50 mL), brine (50 mL),dried (Na₂SO₄), and concentrated in vacuo to afford Part B compound as ayellow oil (7.41 g, 100%).

To a 0° C. solution of Part B compound (7.41 g; 28.5 mmol) and Ph₃P(9.44 g, 35.6 mmol) in CH₂Cl₂ (56 mL) was added CBr₄ (11.94 g, 35.6mmol) portionwise over 10 min. The mixture was warmed to RT over 40 min,then was concentrated to 1/5 of the original volume and hexane (60 mL)was added. The precipitate was filtered off and rinsed with hexane. Thecombined filtrate and rinses were concentrated in vacuo, and the residuewas chromatographed (SiO₂; 95:5 hex:EtOAc) to give Part C compound (10.2g, 100%) as a colorless oil.

To a 0° C. solution of Rieke zinc (23 mL of an activated zinc powdersuspension in THF [containing 5 g of Zn per 100 mL THF], 17.8 mmol) inTHF (18 mL) was added a solution of Part C compound (4.10 g, 13.7 mmol)in THF (18 mL) under Ar. The mixture was stirred at RT for 3 h; excesszinc was filtered off under Ar and the benzylzinc solution was added toa mixture of 1,1′-Bis(diphenylphosphino)ferrocene (dppf) (0.156 g, 0.274mmol) and Bis(dibenzylideneacetone)palladium (0) [Pd(dba)₂] (0.157 g,0.274 mmol) under Ar. The mixture was stirred at RT for 30 min, afterwhich a solution of Example 362 Part A compound (2.47 g, 4.56 mmol) inTHF (18 mL) was added dropwise. The mixture was heated to 65° C. for 12h, then cooled to RT. Saturated aqueous NaHCO₃ (60 mL) was added; solidswere filtered off, and the cake was rinsed with Et₂O. The aqueous phasewas extracted with Et₂O (3×30 mL). The combined organic extracts/rinseswere dried (Na₂SO₄), concentrated in vacuo, and chromatographed (SiO₂;85:15 hexane:EtOAc) to afford Part D compound as a light yellow oil(0.982 g, 46%).

[M+H]⁺=466.7

¹H NMR (400 MHz, CDCl₃) δ 7.17 (m, 5H), 7.02 (t, J=Hz, 1H), 6.70 (m,1H), 6.60 (m, 2H), 4.11 (q, J=7.0 Hz, 2H), 3.66 (s, 2H), 3.40 (s, 2H),2.88 (s, 2H), 2.60-2.39 (m, 4H), 1.15 (t, J=7.0 Hz, 3H), 0.89 (s, 9H),0.10 (s, 6H)

¹³C NMR (400 MHz, CDCl₃) δ 167.7, 155.6, 145.2, 140.6, 137.9, 129.1,128.8, 128.1, 121.7, 120.2, 117.8, 61.8, 60.1, 57.0, 49.0, 38.0, 27.0,25.7, 18.2, 14.2

To a 0° C. solution of Part D compound (0.391 g, 0.842 mmol) andProton-sponge (3 mg) in CH₂Cl₂ (8 mL) was slowly added α-chloroethylchloroformate (0.233 mL, 2.10 mmol). The mixture was heated at 40° C.for 1 h; volatiles were removed in vacuo, and a solution of the residuein MeOH (8 mL) was heated at 40° C. for 1 h. Volatiles were removed invacuo to afford Part E compound as a yellow oil, which was used in thenext reaction without further purification. [M+H]⁺=261.3

To a solution of compound E in 1,4-dioxane/H₂O (10 mL of a 1:1 v/vsolution) was added di-tert-butyl dicarbonate (0.165 g, 0.758 mmol) andNaHCO₃ (0.212 g, 2.53 mmol). The mixture was stirred at RT for 2 h, thenwas partitioned between H₂O (20 mL) and CH₂Cl₂ (15 mL). The aqueousphase was extracted with CH₂Cl₂ (2×15 mL) The combined organic extractswere dried (Na₂SO₄), concentrated in vacuo, and chromatographed (SiO₂;4:1 hex:EtOAc) to give Part F compound as a colorless oil (0.218 g, 72%yield over 2 steps). [M+H]⁺=362.4

Part F Compound (0.218 g, 0.603 mmol) and2-(5-methyl-2-phenyloxazole-4-yl)ethanol (0.184 g, 0.904 mmol) werestripped from dry toluene (3×), then were dissolved in dry toluene (6mL). Bu₃PCHCN (0.20 mL, 0.905 mmol) was added dropwise and the mixturewas heated at 60° C. under Ar for 2 h, then was cooled to RT. Volatileswere removed in vacuo, and the residue was chromatographed (SiO₂;gradient from 5:1 to 7:3 hex:EtOAc) to afford Part G compound as acolorless oil (0.297 g, 90%).

[M+H]⁺=547.7

Part G compound was deprotected (removal of N-Boc group) using theAcCl/MeOH procedure described in Example 370 (Part E) to give Part Hcompound (0.263 g; 100% yield) as an oil.

[M+H]⁺=447.5

Part H compound (39.1 mg; 0.081 mmol) was reacted (as for Example 363)with isobutyl chloroformate (11.6 μL, 0.090 mmol) to give compound I(44.5 mg; 100%) as a light yellow oil, which was used in the nextreaction without further purification. [M+H]⁺=547.6

Part I Compound (22.2 mg; 0.040 mmol) was hydrolyzed under acid (20%HCl/HOAc) conditions as described in Example 362 Part E. The crudeproduct was purified by preparative HPLC (YMC S5 ODS 20×250 mm column;continuous gradient from 50:50 solvent A:B to 100% solvent B; wheresolvent A=90:10:0.1H₂O:CH₃CN:TFA; solvent B=90:10:0.1 CH₃CN:H₂O:TFA) toafford the title compound (38%) as a white solid. [M+H]⁺=519.2

¹H NMR (400 MHz, CD₃OD) δ 7.96 (m, 2H), 7.47 (m, 3H), 7.16 (t, J=7.4 Hz,1H), 6.83-6.80 (m, 3H), 4.21 (t, J=6.7 Hz, 2H), 3.89-3.50 (m, 8H), 2.97(t, J=6.7 Hz, 2H), 2.47 (s, 2H), 2.38 (s, 3H), 2.00-1.60 (m, 1H),0.92-0.71 (br., 6H)

¹³C NMR (100.6 MHz, CD₃OD) δ 169.2, 159.5, 158.5, 155.3, 140.1, 131.6,130.2, 129.1, 128.5, 125.7, 124.6, 120.9, 114.8, 112.1, 71.4, 66.0,46.3, 40.0, 37.2, 27.5, 26.0, 25.6, 18.4, 9.6

EXAMPLES 374-380

Examples 374-380 of the invention were prepared according to the generalprocedures described for the syntheses of Examples 363, 364, 370 and373.

Example No R [M + H]⁺ 374

539.2 375

491.2 376

565.0 377

553.2 378

569.1 379

505.1 380

519.6

EXAMPLE 381

A solution of Example 373 Part I compound (24 mg, 0.044 mmol), LiOH.H₂O(4.2 mg, 0.175 mmol) and MeOH (1 drop) in THF—H₂O (1.5 mL, 2:1 v/v) wasstirred at RT for 3 h. The reaction was acidified to pH 2 with 1 Naqueous HCl, then was extracted with EtOAc (3×5 mL). The combinedorganic extracts were concentrated in vacuo and the residue was purifiedby preparative HPLC (YMC S5 ODS 20×250 mm column; continuous gradientfrom 50:50 solvent A:B to 100% solvent B; where solventA=90:10:0.1H₂O:CH₃CN:TFA; solvent B=90:10:0.1 CH₃CN:H₂O:TFA) to give thetitle compound (11.9 mg, 52%) as a white solid.

[M+H]⁺=519.2

¹H NMR (400 MHz, CD₃OD) δ 7.95 (m, 2H), 7.46 (m, 3H), 7.18 (t, J=7.9 Hz,1H), 6.85-6.66 (m, 4H), 4.22 (br. S, 2H), 4.95-4.85 (m, 3H), 3.40 (m,3H), 2.98 (t, J=6.6 Hz, 2H), 2.90 (m, 1H), 2.38 (s, 3H), 2.10-1.73 (m,3H), 0.94 (d, J=6.6 Hz, 3H), 0.84 (d, J=6.6 Hz, 3H)

¹³C NMR (125.7 MHz, DMSO-d₆, t=100° C.) δ 174.4, 159.2, 159.0, 153.2,145.2, 141.5, 133.4, 130.3, 129.7, 129.3, 128.0, 126.1, 123.7, 121.9,116.0, 115.3, 113.1, 71.9, 70.0, 40.7, 40.2, 39.6, 28.0, 26.4, 25.0,19.2, 10.2

EXAMPLES 382-389

Examples 382-389 of the invention were prepared according to theprocedures described for the synthesis of Example 373 and Example 381.Example No. Structure [M + H]⁺ 382

477.0 383

491.2 384

505.1 385

519.1 386

533.1 387

553.2 388

565.1 389

569.1

EXAMPLE 390

The two individual enantiomers of Example 381 (racemate; 50 mg) wereseparated by preparative HPLC (Chiralpak® AD chiral column; 5 cm×50 cm,20μ, Chiral Technologies Inc; isocratic solvent system: 6%i-PrOH/heptane; Flow rate=40 mL/min). The faster eluting fraction(single enantiomer) was characterized as Example 390 (absolutestereochemistry arbitrarily assigned): retention time=45 min; 22.5 mg,white solid, 90% recovery, >99% e.e., [M+H]⁺=519.2,

[α]₂₄ ^(D)=−108.8° (c=0.358 g/100 mL, MeCN).

The slower eluting fraction (single enantiomer), was characterized asExample 391 (absolute stereochemistry arbitrarily assigned): retentiontime=60 min; 17.6 mg, white solid, 70% recovery, >99% e.e.).[M+H]⁺=519.2, [α]₂₄ ^(D)=+100.3° (c=0.50 g/100 mL, MeCN)

EXAMPLE 391

EXAMPLE 392

To a 0° C. solution of ZnCl₂ in THF (12.65 mL of a 1 M solution, 12.65mmol) was added 4-methoxyphenethyl magnesium chloride in THF (19.5 mL ofa 0.5 M solution, 9.73 mmol) dropwise. After stirring for 40 min at 0°C., bis(dibenzylideneacetone)palladium (0) [Pd(dba)₂] (0.153 g, 0.265mmol) and 1,1′-bis(diphenylphosphino)ferrocene (dppf) (0.152 g, 0.265mmol) were added. The reagent mixture was stirred at RT for 10 min,after which a solution of Example 362 Part A compound (2.4 g, 4.42 mmol)in THF (18 mL) was added dropwise. The reaction was heated at 65° C. for12 h, then cooled to RT and concentrated in vacuo. The residue waspartitioned between CH₂Cl₂ (80 mL) and saturated aqueous NaHCO₃ (40 mL).The aqueous phase was extracted with CH₂Cl₂ (4×30 mL). The combinedorganic extracts were dried (K₂CO₃), concentrated in vacuo and theresidue was chromatographed (SiO₂; 85:15 hex:EtOAc) to afford Part Acompound as a light yellow oil (0.989 g, 59%). [M+H]⁺=380.5

¹H NMR (400 MHz, CDCl₃) δ 7.35-7.24 (m, 5H), 7.15 (d, J=7.9 Hz, 2H),6.83 (d, J=7.4 Hz, 2H), 4.21 (q, J=7.0 Hz, 2H), 3.76 (s, 3H), 3.58 (s,2H), 3.03 (s, 2H), 2.73-2.47 (m, 8H), 1.30 (t, J=7.0 Hz, 3H)

To a 0° C. solution of Part A compound (0.483 g, 1.273 mmol) in CH₂Cl₂(13 mL) was added dropwise BBr₃ in CH₂Cl₂ (3.2 mL of a 1.0 M solution;3.20 mmol). The mixture was stirred at 0° C. for 1.5 h. EtOH (1 mL) andsaturated aqueous NaHCO₃ (10 mL) were subsequently added to quench thereaction. The aqueous phase was further extracted with CH₂Cl₂ (3×10 mL).The combined organic extracts were dried Na₂SO₄ and concentrated invacuo. The residue was chromatographed (SiO₂; 3:1 hex:EtOAc) to affordPart B compound (0.443 g, 95%) as a light yellow solid.

Part B compound (0.443 g, 1.212 mmol) and Example 23 Part A compound(0.426 g, 1.516 mmol) were stripped from dry toluene (3×), then weredissolved in anhydrous MeCN (12 mL) and anhydrous K₂CO₃ (0.503 g, 3.63mmol) was added. The reaction mixture was stirred at 90° C. overnight.Additional Example 23 Part A compound (0.341 g, 1.21 mmol) was added,and the reaction was kept at 90° C. for another 4 h. Volatiles wereremoved in vacuo, and the residue was dissolved in water (15 mL) andextracted with CH₂Cl₂ (3×15 mL). The combined organic extracts weredried (K₂CO₃) and concentrated in vacuo. The residue was chromatographed(SiO₂; 4:1 hex:EtOAc) to afford Part C compound (0.400 g, 60%) as alight yellow oil.

Part C Compound (0.216 g, 0.394 mmol) and Proton Sponge[1,8-bis(dimethylamino)naphthalene] (4.0 mg) were stripped from drytoluene (2×), then dissolved in CH₂Cl₂ (4 mL). To this 0° C. solutionwas added dropwise α-chloroethyl chloroformate (0.10 mL, 0.906 mmol).The reaction was allowed to warm to RT, then heated to 40° C. under Arfor 1 h. Volatiles were removed in vacuo; MeOH (4 mL) was added, and themixture was heated at 50° C. for 1 h. Volatiles were removed in vacuo toafford crude Part D compound (0.156 g, 80% yield) as a light yellow oil,which was used in the next step without further purification.[M+H]⁺=461.5

Part E compound was prepared from Part D compound and isobutylchloroformate according to the procedure described for the synthesis ofExample 363 Part B compound.

The title compound (white solid; 60% overall for 2 steps) was preparedfrom Part E compound by acid-mediated hydrolysis followed bypurification by preparative HPLC according to the procedure describedfor the synthesis of Example 363.

[M+H]⁺=533.5

EXAMPLE 393

A mixture of Example 392 Part A Compound (0.506 g, 1.33 mmol) and 10%Pd/C (1.02 g) in HOAc (14 mL) was stirred under an atmosphere of H₂ (80psi pressure) overnight, after which the catalyst was filtered off. Thefiltrate was concentrated in vacuo to give crude Part A compound as abrown oil.

To a 0° C. solution of crude Part A compound in CH₂Cl₂ (13 mL) was addedBBr₃ (4.0 mL, 4.0 mmol, 1 M in CH₂Cl₂) dropwise over ˜15 min. Themixture was stirred at 0° C. for 1 h. MeOH (1 mL) and saturated aqueousNaHCO₃ (10 mL) was added slowly to quench the reaction, which waspartitioned between water and CH₂Cl₂. The aqueous layer was extractedwith CH₂Cl₂ (2×15 mL). The combined organic extracts were concentratedunder reduced pressure to afford crude Part B compound as a brown oil.

A solution of crude Part B compound, di-tert-butyl dicarbonate (0.291 g,1.334 mmol) and NaHCO₃ (0.448 g, 5.33 mmol) in 1,4-dioxane-H₂O (13.4 mL,1:1 v/v) was stirred at RT for 1 h, then was partitioned between H₂O andEtOAc (15 mL each). The aqueous phase was extracted with EtOAc (2×15mL). The combined organic extracts were dried (Na₂SO₄) and concentratedin vacuo. The residue was chromatographed (SiO₂; 7:3 hex:EtOAc) to givePart C compound as a white solid (0.277 g, 55% yield over 3 steps).

Part C Compound (0.277 g, 0.734 mmol) and2-(5-methyl-2-phenyloxazole-4-yl)ethanol (0.224 g, 1.102 mmol) werestripped from dry toluene (3×), then were dissolved in dry toluene (7.4mL) and Bu₃PCHCN (0.266 g, 1.102 mmol) was added. The mixture was heatedat 50° C. under Ar for 2 h, then cooled to RT and volatiles were removedin vacuo. The residue was purified (SiO₂; 3:1 hex:EtOAc) to give Part Dcompound as a colorless oil (0.373 g, 90%).

The deprotection of the N-Boc group of Part D compound (64 mg, 0.114mmol) was carried out using the AcCl/MeOH procedure described for thesynthesis of Example 370 Part E compound to give Part E compound (56.7mg, 100%) as an oil.

Part F compound was prepared from Part E compound and isobutylchloroformate according to the procedure described for the synthesis ofExample 363 Part B compound.

The title compound (white solid) was prepared from Part F compound byacid-mediated hydrolysis and purified by preparative HPLC according tothe procedure described for the synthesis of Example 363.

[M+H]⁺=535.4

EXAMPLES 394-399

Examples 394-399 of the invention were prepared according to theprocedures described for the synthesis of Example 392 and Example 393.The N-pyrimidine compounds were synthesized using the proceduredescribed for the synthesis of Example 364 Part B compound. Ex- am- ple[M + No. Structure H]⁺ 394

553.5 395

579.5 396

523.4 397

555.4 398

527.3 399

581.4

EXAMPLE 400

The two individual enantiomers of Example 393 (racemate; 30 mg) wereseparated by preparative HPLC: (Chiralcel OJ chiral column; 2 cm×25 cm,Chiral Technologies Inc; isocratic solvent system: 15% EtOH-MeOH (1:1)with 0.1% TFA+85% heptane (0.1% TFA); flow rate=7 mL/min. The fastereluting fraction (enantiomer) was characterized as Example 400 (absolutestereochemistry arbitrarily assigned): retention time=45 min; 13.6 mg,white solid, 90% recovery, >99% e.e., [M+H]⁺=535.1,

[α]₂₄ ^(D)=−10.3° (c=0.15 g/100 mL, MeCN).

The slower eluting fraction (enantiomer), was characterized as Example401 (absolute stereochemistry arbitrarily assigned): retention time=72min; 12.2 mg, white solid, 81% recovery, >99% e.e.). [M+H]⁺=535.2,

[α]₂₄ ^(D)=+9.6° (c=0.54 g/100 mL, MeCN)

EXAMPLE 401

EXAMPLE 402

Example 362 Part A compound (1.93 g, 3.55 mmol) was reacted3-methoxyphenyl magnesium chloride (7.8 mL, 1 M solution in THF, 7.8mmol) according to the procedure described in Example 392 Part A to givePart A compound (0.745 g, 60%) as a light yellow oil.

[M+H]⁺=352.4

¹H NMR (400 MHz, CDCl₃) δ 7.38-7.27 (m, 6H), 6.82 (m, 1H), 6.75-6.70 (m,2H), 3.93 (q, J=7.1 Hz, 2H), 3.77 (s, 3H), 3.67 (s, 2H), 3.28 (s, 2H),2.80-2.56 (m, 4H), 0.90 (t, J=7.1 Hz, 3H)

¹³C NMR (100 MHz, CDCl₃) δ 168.1, 159.1, 144.4, 141.8, 137.3, 129.7,129.0, 128.8, 128.2, 127.1, 125.5, 119.5, 112.8, 112.7, 61.8, 59.9,58.1, 55.0, 48.8, 26.7, 13.4

A mixture of Part A compound (0.241 g, 0.687 mmol) and 10% Pd/C (0.48 g)in HOAc (10 mL) mixture was stirred under an atmosphere of H₂ (80 psi)for 24 h. The catalyst was filtered off, and the filtrate wasconcentrated in vacuo to give crude Part B compound as a brown oil.

To a 0° C. solution of crude Part B compound in CH₂Cl₂ (6.8 mL) wasslowly added BBr₃ (3.41 mL, 3.41 mmol, 1 M in CH₂Cl₂) over 15 min. Themixture was stirred at 0° C. for 1 h. MeOH (1 mL) and saturated aqueousNaHCO₃ (10 mL) were slowly added to quench the reaction. The aqueouslayer was extracted with CH₂Cl₂ (3×10 mL). The combined organic extractswere concentrated in vacuo to give crude Part C compound as a brown oil.

A solution of crude Part C compound, di-tert-butyl dicarbonate (0.151 g,0.687 mmol) and NaHCO₃ (0.230 g, 2.74 mmol) in 1,4-dioxane-H₂O (4.0 mL,1:1 v/v) was stirred at RT for 1 h. H₂O (15 mL) was added and themixture was extracted with EtOAc (3×10 mL). The combined organicextracts were dried (Na₂SO₄) and concentrated in vacuo. The residue waschromatographed (SiO₂; 3:1 hex:EtOAc) to give Part D compound as acolorless oil (0.106 g, 45% yield over 3 steps).

Part D Compound (0.105 g, 0.300 mmol) and2-(5-methyl-2-phenyloxazole-4-yl)ethanol (0.092 g, 0.450 mmol) werestripped from dry toluene (3×), then were dissolved in dry toluene (3.0mL) and Bu₃PCHCN (0.108 g, 0.450 mmol) was added. The mixture was heatedat 50° C. under Ar for 2 h, then cooled to RT and concentrated in vacuo.The residue was chromatographed (SiO₂; 3:1 hex:EtOAc) to give Part Ecompound as a colorless oil (0.119 g, 75%).

To MeOH (12.5 mL) at 0° C. was slowly added acetyl chloride (3.2 mL).The solution was stirred 0° C. for 1 h, then was added to Part Ecompound (0.119 g, 0.223 mmol). The mixture was stirred at 0° C. for 15min and then gradually warmed to RT. Volatiles were removed in vacuo togive crude Part F compound (99.9 mg, 95%), which was used in the nextreaction without further purification.

[M+H]⁺=435.5

Part G compound was prepared from Part F compound and isobutylchloroformate according to the procedure described for the synthesis ofExample 363 Part B compound.

The title compound (white solid) was prepared from Part G compound byacid-mediated hydrolysis and purified by preparative HPLC according tothe procedure described for the synthesis of Example 363.

[M+H]⁺=507.2

EXAMPLES 403-405

Examples 403-405 of the invention were prepared according to theprocedures described for the synthesis of Example 402. The N-pyrimidinecompounds were synthesized using the procedure described for thesynthesis of Example 364 Part B compound. Exam- ple No. Structure [M +H]⁺ 403

527.2 404

553.2 405

499.2

EXAMPLE 406

To a solution of Example 362 Part A Compound (1.68 g, 3.11 mmol) and3-hydroxyphenylboronic acid (0.86 g, 6.22 mmol) in 1,4-dioxane (31 mL)were added Pd(PPh₃)₄ (1.08 g, 0.933 mmol), LiCl (0.263 g, 6.21 mmol),and aqueous K₂CO₃ (3.1 mL of a 2 M solution, 6.21 mmol). The mixture washeated at 115° C. under Ar for 12 h, then was cooled to RT. Precipitateswere filtered off. H₂O (40 mL) was added, and the mixture was extractedwith CH₂Cl₂ (3×20 mL). The combined organic extracts were dried (NaHCO₃)and concentrated in vacuo. The residue was chromatographed (SiO₂; 7:3hex:EtOAc) to give Part A compound (1.03 g, 95%) as a colorless oil.

¹H NMR (500 MHz, CDCl₃) δ 8.33 (br s, 1H), 7.37-6.34 (m, 9H), 3.85 (q,t=7.0 Hz, 2H), 3.70 (s, 2H), 3.24 (s, 2H), 2.76 (m, 2H), 2.62 (m, 2H),0.83 (t, J=7.0 Hz, 3H)

¹³C NMR (125 MHz, CDCl₃) δ 168.3, 156.2, 144.2, 141.3, 135.4, 129.7,129.2, 128.3, 127.6, 125.4, 118.7, 115.0, 114.0, 107.5, 103.0, 61.9,60.3, 57.3, 48.8, 26.0, 13.3

Part A compound (1.0 g, 2.97 mmol) and Example 23 Part A compound (1.04g, 3.70 mmol) were stripped from dry toluene (3×), then were dissolvedin anhydrous MeCN (30 mL); finally anhydrous K₂CO₃ (1.64 g, 11.86 mmol)was added. The reaction was stirred at 90° C. overnight. More Example 23Part A compound (0.416 g, 1.48 mmol) was added and the mixture wasstirred at 90° C. for another 4 h. Volatiles were removed in vacuo, andthe residue was dissolved in water (30 mL) and extracted with CH₂Cl₂(3×20 mL). The combined organic extracts were dried (K₂CO₃) andconcentrated in vacuo. The residue was chromatographed (SiO₂; 7:3hex:EtOAc) to give Part B compound (0.93 g, 60%) as a light yellow oil.

Part B compound (0.594 g; 1.14 mmol) was converted to Part C Compoundusing the procedure described in Example 373 Part E. Part C compound wasobtained as an oil, which was used in the next step without furtherpurification. [M+H]⁺=433.5

To a solution of Part C compound in 1,4-dioxane/H₂O (22 mL of a 1:1 v/vsolution) was added di-tert-butyl dicarbonate (0.25 g, 1.137 mmol) andNaHCO₃ (0.24 g, 2.84 mmol). The mixture was stirred at RT for 2 h, thenwas partitioned between H₂O (20 mL) and CH₂Cl₂ (15 mL). The aqueousphase was extracted with CH₂Cl₂ (2×15 mL). The combined organic extractswere dried (Na₂SO₄), concentrated in vacuo, and chromatographed (SiO₂;4:1 hex:EtOAc) to give Part D compound as a colorless oil (0.55 g, 91%yield over 2 steps). [M+H]⁺=533.6

To a solution of Part D compound (0.55 g, 1.04 mmol) in THF (10 mL) at−78° C. was added LiAlH₄ in THF (1.56 mL of a 1 M solution, 1.56 mmol).The reaction was gradually warmed to 10° C. and stirred for 12 h.Saturated aqueous NH₄Cl solution (10 mL) was added; precipitates werefiltered off. The aqueous phase was extracted with CH₂Cl₂ (3×10 mL). Thecombined organic extracts were dried (Na₂SO₄), concentrated in vacuo andchromatographed (SiO₂; 55:45 hex:EtOAc) to give Part E compound (0.389g, 76%) as a white solid. [M+H]⁺=491.6

To a 0° C. solution of Part E Compound (0.389 g, 0.792 mmol) and PPh₃(0.262 g, 0.991 mmol) in CH₂Cl₂ (8 mL) was added CBr₄ (0.332 g, 0.991mmol) portionwise. The mixture was slowly warmed to RT and stirred at RTfor 2 h. Volatiles were removed in vacuo, and the residue waschromatographed (SiO₂; continuous gradient from 90:10 to 85:15hex:EtOAc)) to afford Part F compound (0.407 g, 93%) as a light yellowoil.

To a solution of Part F compound (0.371 g, 0.671 mmol) and (PPh₃P)₄Pd(0.155 g, 0.134 mmol) in MeOH (8 mL) was added KHCO₃ (0.268 g, 2.68mmol). The mixture stirred at RT overnight under a pressure of 100 psiof CO gas in a stainless steel bomb. Volatiles were removed in vacuo andthe residue was taken up in H₂O (10 mL) and extracted with CH₂Cl₂ (3×10mL). The combined organic extracts were dried (Na₂SO₄), concentrated invacuo, and chromatographed (4:1 hex:EtOAc) to afford Part G compound(0.218 g, 61%) as a colorless oil.

[M+H]⁺=533.6

¹H NMR (400 MHz, CDCl₃) δ 7.91 (dd, J=2.0 & 7.9 Hz, 2H), 7.33 (m, 3H),7.17 (s 1H), 7.16 (d, J=10.6 Hz, 1H), 6.76 (d, J=6.3 Hz, 1H), 6.68 (d,J=6.3 Hz, 1H), 4.16 (t, J=6.6 Hz, 2H), 3.96 (s, 2H), 3.56 (s, 3H), 3.50(t, J=5.5 Hz, 2H), 2.91 (m, 4H), 2.30 (s, 3H), 2.15 (br. s, 2H), 1.39(s, 9H)

Compound G (0.218 g; 0.410 mmol) was subjected to the acetylchloride/MeOH deprotection conditions (as for Example 402 Part Fcompound) for the deprotection of the N-Boc group to give Part Hcompound as the HCl salt (0.171 g; 89%). [M+H]⁺=433.5

Part I compound was prepared from Part H compound and isobutylchloroformate according to the procedure described for the synthesis ofExample 363 Part B compound.

The title compound (white solid) was prepared from Part G compound byacid-mediated hydrolysis and purified by preparative HPLC according tothe procedure described for the synthesis of Example 363.

[M+H]⁺=519.3

EXAMPLES 407-408

Examples 407-408 of the invention were prepared according to theprocedures described for the synthesis of Example 406. The N-pyrimidinecompound was synthesized using the procedure described for the synthesisof Example 364 Part B compound. Exam- ple No Structure [M + H]⁺ 407

539.2 408

565.1

EXAMPLE 409

A mixture of Example 406 Part H compound (13.2 mg; 0.0282 mmol) and Pd/C(40 mg, 10%) in HOAc (10 mL) was stirred under an atmosphere of H₂(60-70 psi) overnight to give Part A compound (12.2 mg; 100%).

Part B compound was prepared from Part A compound and isobutylchloroformate according to the procedure described for the synthesis ofExample 363 Part B compound.

The title compound (white solid) was prepared from Part B compound byacid-mediated hydrolysis and purified by preparative HPLC according tothe procedure described for the synthesis of Example 363.

[M+H]⁺=521.1

EXAMPLE 410

Example 410 was prepared according to the general procedures describedfor the synthesis of Example 409.

[M+H]⁺=541.1

EXAMPLE 413

The title compound was prepared from Example 406 Part B compound byacid-mediated hydrolysis according to the procedure described for thesynthesis of Example 363. The crude product was purified by preparativeHPLC (also according to the procedure of Example 363) to give the titlecompound (10.7 mg, 56.7%) as a white solid.

[M+H]⁺=495.5

EXAMPLE 414

(Ref. Adlington, R. M. et al. J. Med. Chem. 2001, 44, 1491)

To a 45° C. mixture of Example 419 Part A compound (3.0 g, 10.93 mmol)

and Et₃N (1.6 mL, 11.5 mmol) in dry toluene (70 mL) under N₂ was addeddropwise a solution of 3-(4-benzyloxyphenyl)-propionyl chloride(prepared in the same manner as Example 419 Part E compound, butstarting from 3-(4-hydroxyphenyl)propionic acid; 2.93 g in 5 mL toluene;10.93 mmol) over 45 min. The solution was stirred at 45° C. for another4 h, cooled to RT and aqueous HCl (9 mL of concentrated HCl in 66 mLH₂O) was added. The mixture was stirred at RT for 16 h, then extractedwith EtOAc (200 mL). The combined organic extracts were dried (Na₂SO₄),concentrated in vacuo and the residue was chromatographed (SiO₂;continuous gradient using hex:EtOAc from 100% hex to 100% EtOAc) to givePart A compound (1.71 g, 39%) as a yellow solid.

[M−H⁺]=400.1.

A mixture of Part A compound (108 mg; 0.269 mmol) in THF (6 mL) andLiBH₄ (8 mg, 0.367 mmol) was stirred at RT overnight, then waspartitioned between saturated aqueous NaHCO₃ and EtOAc. The aqueousphase was extracted with EtOAc and the combined organic extracts werewashed with brine, dried (Na₂SO₄), and concentrated in vacuo. Theresidue was chromatographed (SiO₂; continuous gradient from 0 to 100%EtOAc-hexanes) to afford Part B compound as a white solid (60 mg, 55%).[M+H]⁺=404.3.

A mixture of Part B compound (60 mg; 0.149 mmol) and 10% Pd/C (30 mg) inEtOAc (10 mL) was stirred under an atmosphere of H₂ (1 atm) at RT for 5h. The catalyst was filtered off and the filtrate was concentrated invacuo to give Part C compound (45 mg, 97%) as a colorless oil.

[M+Na]⁺=336.2.

A mixture of Part C compound (45 mg; 0.144 mmol), Example 23 Part Acompound (62 mg; 0.22 mmol), and powdered K₂CO₃ (45 mg; 0.33 mmol) inCH₃CN (8 mL) was heated at reflux overnight, then cooled to RT andpartitioned between EtOAc (25 mL) and H₂O (25 mL). The organic phase waswashed with water, brine, dried (Na₂SO₄) and concentrated in vacuo. Theresidue was chromatographed (SiO₂; continuous gradient from 100% hex to100% EtOAc) to give Part D compound (30 mg; 42%) as a colorless oil.

[M+H]⁺=499.4.

To a dispersion of Dess-Martin periodinane (48 mg, 0.11 mmol) in CH₂Cl₂(3 mL) was added dropwise a solution of Part D compound (30 mg, 0.06mmol) in CH₂Cl₂ (3 mL) and the resulting mixture was stirred at RT for 7h. Volatiles were removed in vacuo and the residue was chromatographed(SiO₂; continuous gradient from 100% hex to 100% EtOAc) to yield Part Ecompound (19.6 mg, 66%) as a pale yellow oil.

[M−H⁺]=495.3.

To a solution of Part E compound (19 mg, 0.04 mmol) in acetone (1.5 mL)was added Jones reagent (4 drops). The reaction was stirred at RT for 3h and then partitioned between water and EtOAc (20 mL each). The organicphase was washed with H₂O, brine, dried (Na₂SO₄) and concentrated invacuo. The residue was purified by preparative HPLC (YMC reverse-phaseODS 20×100 mm column; flow rate=20 mL/min; 10 min continuous gradientfrom 70:30 B:A to 100% B, where solvent A=90:10:0.1H₂O:MeOH:TFA andsolvent B=90:10:0.1 MeOH:H₂O:TFA) to give the title compound (4.9 mg;25%).

[M+H]⁺=513.3

¹H NMR (400 MHz, CDCl₃) δ 2.38 (s, 3H), 2.87 (dd, J=14.9, 7.47 Hz, 1H),2.95-3.1 (m, 3H), 3.75 (s, 3H), 3.7-3.8 (m, 1H), 4.05-4.15 (br. t,J=6.15 Hz, 2H), 4.58 (d, J=5.72 Hz, 1H), 6.69 (d, J=8.36 Hz, 2H), 6.82(d, J=8.8 Hz, 2H), 7.01 (d, J=8.36 Hz, 2H), 7.27 (d, J=9.24 Hz, 2H),7.35-7.45 (m, 3H), 7.92 (d, J=7.48 Hz, 2H).

EXAMPLE 414 Alternative Sequence

To a solution of Example 414 Part A compound (979 mg, 2.44 mmol) inacetone (75 mL) was added Jones reagent (2.6 mL) dropwise. The reactionwas stirred at RT for 0° C. for 1.5 h, concentrated in vacuo. Theresidue was partitioned between water and EtOAc (100 mL each). Theorganic phase was washed with H₂O, brine, dried (Na₂SO₄) andconcentrated in vacuo to give the crude Part G compound (787 mg) whichwas used in the next step without further purification.

[M+H]⁺=418.5.

To a 0° C. solution of the crude Part G compound in CH₂Cl₂:CH₃OH (1:1,20 mL) was added TMSCHN₂ (3 mL of a 2M solution in hexanes, 6 mmol)dropwise and the mixture was stirred at 0° C. for 1 h. Volatiles wereremoved in vacuo and the residue was chromatographed (SiO₂; continuousgradient from 100% hex to 100% EtOAc) to give Part H compound (477 mg,45% for 2 steps) as an off-white solid.

[M+H]⁺=432.5.

A mixture of Part H compound (76 mg; 0.176 mmol) and 10% Pd/C (33 mg) inEtOAc (5 mL) was stirred overnight under an atmosphere of H₂ (1 atm) atRT. HPLC indicated incomplete conversion. More 10% Pd/C (37 mg) wasadded and the mixture was stirred for a further 2 h under H₂. Thecatalyst was filtered off and the filtrate was concentrated in vacuo togive Part I compound (49 mg, 81%) as a white solid.

A mixture of Part I compound (49 mg; 0.144 mmol), Example 23 Part Acompound (65 mg; 0.23 mmol) and powdered K₂CO₃ (40 mg; 0.29 mmol) inCH₃CN (10 mL) was heated under reflux overnight, at which point HPLCindicated incomplete conversion. More Example 23 Part A compound (63 mg;0.22 mmol) and K₂CO₃ (49 mg; 0.36 mmol) were added and the mixtureheated at reflux for a further 12 h, then was cooled to RT andpartitioned between EtOAc and H₂O (25 mL each). The aqueous phase wasextracted with EtOAc (×2) and the combined organic extracts were washedwith water, brine, dried (Na₂SO₄) and concentrated in vacuo. The residuewas chromatographed (SiO₂; continuous gradient from 100% hexane to 100%EtOAc) to give Part J compound (68 mg; 83%) as a colorless oil.

[M+H]⁺=526.8.

A solution of Part H compound (67 mg, 0.127 mmol) and LiOH.H₂O (10 mg,0.238 mmol) in H₂O (0.3 mL) in THF (1.2 mL) was stirred for 5 h at RT,then was partitioned between EtOAc (20 mL) and aqueous 1N HCl (10 mL).The aqueous phase was extracted with EtOAc (×2) and the combined organicextracts were washed with brine, dried (Na₂SO₄), and evaporated in vacuoto yield the title compound (60.5 mg; 93%) as a white solid.

[M+H]⁺=513.4.

EXAMPLE 415

The racemic Example 414 Part J compound (31 mg) was separated into thetwo individual enantiomers by preparative HPLC (Chiracel chiral AD 5×50cm column; flow rate=45 mL/min; isocratic mobile phase 65:35 A:B, wheresolvent A=heptane+0.1% TFA and solvent B=isopropanol+0.1% TFA). Thefaster eluting fraction was concentrated in vacuo to give Example 415.

[M+H]⁺=513.4; [α]_(D)=−16.0° (c=0.075, CDCl₃, 24° C.);

The absolute stereochemistry is arbitrarily assigned. The ¹H NMRspectrum is identical to Example 414.

Chiral analytical HPLC (Daicel Chiralcel AD 4.6×250 mm column, flowrate=1 mL/min; isocratic conditions=65:35 A:B, where A=heptane+0.1% TFAand B=IPA+0.1% TFA; detector wavelength=264 nm): retention time=9.91min; ee=96%.

EXAMPLE 416

The slower eluting fraction in the above separation was evaporated invacuo to give Example 416.

[M+H]⁺=513.4; [α]_(D)=+20.77° (c=0.062, CDCl₃, 24° C.);

Chiral analytical HPLC (Daicel Chiralcel AD 4.6×250 mm column, flowrate=1 mL/min; isocratic conditions=65:35 A:B, where A=heptane+0.1% TFAand B=IPA+0.1% TFA; detector wavelength=264 nm): retention time=15.96min; ee=>99%. Absolute stereochemistry is arbitrarily assigned. ¹H NMR:identical to Example 414.

EXAMPLE 417

To a 0° C. solution of Example 414 Part H compound (366 mg; 0.85 mmol)in CH₃CN (15 mL) was added aqueous ammonium cerium nitrate (990 mg; 1.8mmol in 5 mL H₂O). The reaction mixture was stirred at 0° C. for 3 h,then EtOAc (100 mL) was added. The organic phase was washed withsaturated aqueous Na₂SO₃ (15 mL), dried (Na₂SO₄) and concentrated invacuo. The residue was chromatographed (SiO₂; continuous gradient from100% hex to 100% EtOAc) to give Part A compound (173 mg; 63%) as ayellow solid.

¹H NMR (400 MHz, CDCl₃) δ 2.81 (dd, J=15.4, 8.4 Hz, 1H), 3.00 (dd,J=14.9, 7.9 Hz, 1H), 3.62 (s, 3H), 3.83 (br. q, J=7.92 Hz, 1H), 4.28 (d,J=5.72 Hz, 1H), 4.98 (s, 2H), 6.14 (br. s, 1H), 6.89 (d, J=8.32 Hz, 2H),7.12 (d, J=8.36 Hz, 2H), 7.26-7.43 (m, 5H); [M−H⁺]=324.6

To a solution of the Part A compound (57.7 mg, 0.178 mmol) in DCE (2.5mL) was added p-t-butyl phenylboronic acid (66 mg, 0.37 mmol), Cu(OAc)₂(34 mg 0.187), Et₃N (74 μL, 0.53 mmol), pyridine (55 μL, 0.68 mmol) and4 Å molecular sieves (33 mg; pre-dried at 400° C. overnight). Air wasallowed to pass into the reaction mixture, which was stirred at RT for1.5 h. The volatiles were removed in vacuo and the residue waschromatographed (SiO₂; continuous gradient from 100% hex to 100% EtOAc)to give Part B compound (49 mg, 60%) as a colorless oil.

[M+H]⁺=458.5.

A mixture of Part B compound and 10% Pd/C (49 mg) in EtOAc (5 mL) wasstirred under an atmosphere of H₂ (1 atm) at RT for 2 h. The catalystwas filtered off and the filtrate was concentrated in vacuo to give PartC compound, which was used in the next step without furtherpurification.

[M+H]⁺=368.4.

A mixture of crude Part C compound, Example 23 Part A compound (65 mg;0.23 mmol) and powdered K₂CO₃ (70 mg; 0.51 mmol) in CH₃CN (3 mL) wasstirred at 95° C. for 16 h, then cooled to RT and partitioned betweenEtOAc (20 mL) and aqueous 1N HCl (10 mL). The aqueous layer wasextracted with EtOAc (×2) and the combined organic extracts were washedwith brine, dried (Na₂SO₄) and concentrated in vacuo. The residue waschromatographed (SiO₂; continuous gradient from 100% hex to 100% EtOAc)to afford Part D compound (50.3 mg, 85%) as a colorless oil.

A solution of Part D compound (50 mg, 0.091 mmol) and LiOH.H₂O (9 mg,0.214 mmol) in H₂O (0.5 mL) and THF (3 mL) was stirred for 7 h at RT,then partitioned between EtOAc (20 mL) and aqueous 1N HCl (10 mL). Theaqueous layer was extracted with EtOAc (×2) and the combined organicextracts were washed with brine, dried (Na₂SO₄), and concentrated invacuo. The residue was purified by preparative HPLC (YMC reverse-phaseODS 20×100 mm column; flow rate=20 mL/min; 10 min continuous gradientfrom 60:40 B:A to 100% B, where solvent A=90:10:0.1H₂O:MeOH:TFA andsolvent B=90:10:0.1 MeOH:H₂O:TFA) to give Part E compound.

Part E compound was separated into the two individual enantiomers bypreparative HPLC (Chiracel chiral AD 5×50 cm column; flow rate=45mL/min; isocratic mobile phase 85:15 A:B, where solvent A=Heptane+0.1%TFA and solvent B=IPA+0.1% TFA). The faster eluting fraction wasevaporated in vacuo to give Example 417 (15 mg, 31% yield; 50% oftheoretical recovery).

[M+H]⁺=539.4.

Absolute stereochemistry is tentatively assigned.

¹H NMR: δ 1.21 (s, 9H), 2.33 (m, 3H), 2.82 (dd, J=14.94, 7.9 Hz, 1H),2.92-3.05 (m, 3H), 3.72 (q, J=7.48 Hz, 1H), 3.95-4.1 (m, 2H), 4.54 (d,J=6.16 Hz, 1H), 6.64 (d, J=8.36 Hz, 2H), 6.96 (d, J=8.36 Hz, 2H),7.18-7.4 (m, 7H), 7.86 (d, J=7.48 Hz, 2H), 9.98 (br. s, 1H).

Chiral analytical HPLC (Daicel Chiralcel AD 4.6×250 mm column, flowrate=1 mL/min; isocratic conditions=60:40 A:B, where A=heptane+0.1% TFAand B=IPA+0.1% TFA; detector wavelength=254 nm): retention time=10.96min; ee=99%, Purity=85% (contained 15% trans-isomer).

EXAMPLE 418

The slower eluting fraction in the above separation was evaporated invacuo to give Example 418 (8 mg, 16% yield; 50% of theoreticalrecovery).

[M+H]⁺=539.4

Absolute stereochemistry is arbitrarily assigned. ¹H NMR: Identical toExample 417.

Chiral analytical HPLC (Daicel Chiralcel AD 4.6×250 mm column, flowrate=1 mL/min; isocratic conditions=60:40 A:B, where A=heptane+0.1% TFAand B=IPA+0.1% TFA; detector wavelength=254 nm): retention time=21.84min; ee=99%, Purity=99%.

EXAMPLE 419

To a solution of p-anisidine (12.3 g; 0.1 mol) in MeOH (60 mL) at 58° C.was added glyoxal (13.4 g, 40% solution in H₂O, 0.05 mol) over 2 min.The reaction mixture was stirred at 58° C. for another 2 min, thencooled to RT. The mixture was filtered to give Part A compound as ayellow solid (11.0 g, 82%).

To a solution of 3-(3-hydroxyphenyl)propionic acid (18.5 g, 0.11 mol) inMeOH (150 mL) at RT was added concentrated H₂SO₄ (3 mL). The reactionmixture was stirred at 50° C. for 1 h. Volatiles were removed in vacuoand the residue was partitioned between saturated aqueous NaHCO₃ (70 mL)and EtOAc (400 mL). The organic phase was dried (MgSO₄) and concentratedin vacuo to give crude Part B compound (20.0 g, 99%) as an oil.

A mixture of Part B compound (20.0 g, 0.11 mol), benzyl bromide (13.5ml, 0.113 mol) and powdered K₂CO₃ (22.7 g, 0.164 mol) in CH₃CN (400 mL)was stirred at 70° C. for 12 h, then cooled to RT and filtered. Thefiltrate was concentrated in vacuo to give Part C compound (30.0 g;100%) as an oil.

A solution of Part C compound (30 g, 0.111 mol) and aqueous LiOH (5.57 gin 300 mL H₂O, 0.132 mol) in THF (300 mL) was stirred at RT for 16 h,after which more LiOH.H₂O (1.0 g, 0.238 mmol) was added. The reactionwas stirred at RT for another 36 h, then acidified to pH 4 withconcentrated HCl. Organic volatiles were removed in vacuo and theaqueous phase was extracted with EtOAc (2×100 mL). The combined organicextracts were dried (MgSO₄) and concentrated in vacuo to give Part Dcompound (28.1 g, 99%).

To a 0° C. solution of Part D compound (28.1 g, 0.111 mol) in CH₂Cl₂(100 mL) were added DMF (0.5 mL) and oxalyl chloride (20 mL, 0.229 mol)over 75 min. The reaction was stirred at RT for 1 h. Volatiles wereremoved in vacuo and the residue was distilled (Kugelrohr; bp=200° C. @0.1 mm Hg) to give Part E compound (24.2 g; 80%) as a clear oil.

Ref: Adlington, R. M. et al J. Med. Chem. 2001, 44, 1491

To a mixture of Part A compound (3.8 g, 0.014 mol) and Et₃N (3.39 ml,0.024 mol) in dry toluene (110 mL) at 40° C. under N₂ was added dropwisea solution of Part E compound (6.77 g in 5 mL toluene; 0.0247 mol) over2.5 h. The reaction was stirred at 35-40° C. for another 1.5 h, thencooled to RT and aqueous HCl (20 mL of conc. HCl in 130 mL H₂O) wasadded. The mixture was stirred at RT for 16 h and extracted with EtOAc(250 mL). The combined organic extracts were dried (Na₂SO₄),concentrated in vacuo, and the residue was recrystallized from Et₂O togive Part F compound. In addition, the combined mother liquors wereconcentrated in vacuo, and the residue was chromatographed (SiO₂;continuous gradient from 100% hex to 55:45 hex:EtOAc over 35 min, 55:45hex:EtOAc for 10 min) to give additional Part F compound (combinedrecovery=4.03 g, 80%) as a solid. ¹H NMR (400 MHz, CDCl₃) δ 2.87 (dd,J=14.4, 9.7 Hz, 1H), 3.30 (dd, J=9.7, 6.2 Hz, 1H), 3.77 (s, 3H), 4.02(dt, J=9.7, 6.2 Hz, 1H), 4.56 (dd, J=6.2, 2.7 Hz, 1H), 5.05 (s, 2H),6.86-7.50 (m, 13H), 9.60 (d, J=2.7 Hz, 1H);

[M+H]⁺=402.3.

A mixture of Part F compound (2.0 g, 4.98 mmol) and 10% Pd/C (1.85 g) inEtOAc (150 mL) was stirred under an atmosphere of H₂ (60 psi) at RT for24 h, at which point the reaction was complete by HPLC. The catalyst wasfiltered off (Celite®) and the filtrate was concentrated in vacuo togive Part G compound (1.42 g, 91%) as a white foam.

A mixture of Part G compound (1.42 g; 4.53 mmol), Example 23 Part Acompound (1.91 g; 6.79 mmol) and powdered K₂CO₃ (1.37 g; 9.93 mmol) inCH₃CN (40 mL) was stirred at 85° C. for 22 h. At this point analyticalHPLC indicated that all starting material had been consumed. Thereaction mixture was partitioned between Et₂O (200 mL) and H₂O (50 mL).The organic phase was washed with water (2×50 mL), dried (MgSO₄) andconcentrated in vacuo. The residue was chromatographed (SiO₂; stepwisegradient from 5:1 to 2:1 hex:EtOAc) to give Part H compound (1.36 g;60%) as a white foam.

To a mixture of Dess-Martin periodinane (116 mg; 0.27 mmol) in CH₂Cl₂(1.3 mL) at RT was added a solution of Part H compound (100 mg; 0.20mmol) in CH₂Cl₂ (1.3 mL). The reaction was stirred at RT for 30 min.Volatiles were removed in vacuo. The residue was chromatographed (SiO₂;2:1 hex:EtOAc) to give Part I compound (96 mg; 96%) as an oil.

To a 0° C. solution of Part I compound (96 mg, 2.23 mmol) in acetone (75mL) was added Jones reagent (2.25 mL) dropwise. The reaction was stirredat RT for 30 min, after which volatiles were removed in vacuo and theresidue was partitioned between water (60 mL) and EtOAc (200 mL). Theorganic phase was dried (MgSO₄) and concentrated in vacuo to give thecrude product, which was filtered through SiO₂ (100% EtOAc). Volatileswere removed in vacuo and the residue was purified by preparative HPLC(YMC reverse-phase ODS 20×100 mm column; flow rate=20 mL/min; 10 mincontinuous gradient from 70:30 B:A to 100% B+10 min hold-time at 100% B,where solvent A=90:10:0.1H₂O:MeOH:TFA and solvent B=90:10:0.1MeOH:H₂O:TFA) to give Example 419 (32 mg; 32%).

[M+H]⁺=513.4

¹H NMR (400 MHz, CDCl₃) δ 2.40 (s, 3H), 2.99 (t, J=8.7 Hz, 2H), 3.23(dd, J=14.5, 12.3 Hz, 1H), 3.32 (dd, J=14.5, 3.5 Hz, 1H), 3.78 (s, 3H),3.83-3.92 (m, 1H), 4.20-4.45 (m, 2H), 4.50 (d, J=5.7 Hz, 1H), 6.80-6.98(m, 5H), 7.20-7.50 (m, 6H), 7, 92-7.98 (m, 2H)

EXAMPLE 420

The individual enantiomers of Example 419, Part J compound wereseparated by preparative HPLC (Chiracel chiral OD 5×50 cm column; flowrate=45 mL/min; isocratic mobile phase 70:30 A:B, where solventA=Heptane+0.1% TFA and solvent B=isopropanol+0.1% TFA). The fastereluting fraction yielded Example 420. [M+H]⁺=513.2; [α]_(D)=−74.8°(c=0.16, CDCl₃, 25° C.); Absolute stereochemistry is tentativelyassigned. ¹H NMR: identical to Example 419. Chiral analytical HPLC(Daicel Chiralcel AD 4.6×250 mm column): flow rate=1 mL/min; isocraticconditions=70:30 A:B, where A=heptane+0.1% TFA and B=isopropanol+0.1%TFA; detector wavelength=264 nm; retention time=7.89 min; ee>99%.

EXAMPLE 421

The slower eluting fraction from the above chiral separation (Example420) yielded Example 421. (The isocratic mobile phase changed to 60:40A:B after the faster eluting enantiomer came out, where solventA=Heptane+0.1% TFA and solvent B=IPA+0.1% TFA); [M+H]⁺=513.4;[α]_(D)=+58.8° (c=0.16, CDCl₃, 25° C.); Absolute stereochemistry istentatively assigned. ¹H NMR: identical to Example 419.An alternative method was developed for preparation of Examples 420 and421.

To a 0° C. solution of Example 419, part J compound (800 mg, 1.56 mmol)in CH₂Cl₂/MeOH (8.3 mL/8.3 mL) was added a solution of TMSCHN₂ (3.7 mLof a 2M solution in hexane; 0.074 mmol). The mixture was stirred at RTfor 30 min. Volatiles were removed in vacuo and the residue waschromatographed (SiO₂; continuous gradient from 100% hex to 60:40hex:EtOAc over 30 min, 60:40 hex:EtOAc for 10 min) to give Part Acompound (0.4 g, 49%). [M+H]⁺=527.2.

The two enantiomers of the racemate (Part A compound) were separated bypreparative HPLC (Chiralcel chiral OD 5×50 cm column; flow rate=45mL/min; isocratic mobile phase 60:40 A:B, where solvent A=Heptane+0.1%TFA and solvent B=IPA+0.1% TFA). The faster eluting fraction yieldedPart B compound and slowing eluting enantiomer afforded Part C compoundbelow (the isocratic mobile phase changed to 20:80 A:B after fractionscontaining faster eluting enantiomer were collected, where solventA=Heptane+0.1% TFA and solvent B=IPA+0.1% TFA). Chiral analytical HPLC(Daicel Chiralcel OD 4.6×250 mm column): flow rate=1.5 mL/min; isocraticconditions=60:40 A:B, where A=heptane and B=IPA, detector wavelength=264nm; retention time=32.9 min;

Chiral analytical HPLC (Daicel Chiralcel OD 4.6×250 mm column): flowrate=1.5 mL/min; isocratic conditions=60:40 A:B, where A=heptane andB=IPA, detector wavelength=264 nm; retention time=42.7 min;

To a solution of Part B compound (146 mg, 0.277 mmol) in THF (6 mL) wasadded a solution of aqueous LiOH (23.3 mg in 3 mL H₂O, 0.554 mmol). Thereaction mixture was stirred at RT for 16 h after which it was acidifiedto pH 3 with excess aqueous 1 M HCl, then organic solvents were removedin vacuo. The residual aqueous phase was extracted with EtOAc (2×15 mL).The combined organic extracts were successively washed with H₂O andbrine (50 mL each), dried (Na₂SO₄), filtered and concentrated in vacuoto give Example 421 compound as a white solid (120 mg; 85%).[M+H]⁺=513.2; [α]_(D)=+83.1° (c=0.16, CDCl₃, 25° C.).

¹H NMR: identical to Example 419.

Chiral analytical HPLC (Daicel Chiralcel AD 4.6×250 mm column): flowrate=1 mL/min; isocratic conditions=70:30 A:B, where A=heptane+0.1% TFAand B=IPA+0.1% TFA; detector wavelength=264 nm; retention time=12.9 min;ee>93%

A solution of Part C compound (90 mg, 0.171 mmol) in THF (4 mL) andaqueous LiOH (14.3 mg in 1.8 mL H₂O, 0.34 mmol) was stirred at RT for 16h, then was acidified to pH 3 with excess aqueous 1 M HCl. The organicvolatiles were removed in vacuo. The residual aqueous phase wasextracted with EtOAc (2×15 mL). The combined organic extracts weresuccessively washed with H₂O and brine (50 mL each), dried (Na₂SO₄) andconcentrated in vacuo to give Example 420 compound as a white solid (70mg; 80%); [M+H]⁺=513.2; [α]_(D)=−82.3° (c=0.18, CDCl₃, 25° C.).

¹H NMR: identical to Example 419.

Chiral analytical HPLC (Daicel Chiralcel AD 4.6×250 mm column): flowrate=1 mL/min; isocratic conditions=70:30 A:B, where A=heptane+0.1% TFAand B=IPA+0.1% TFA; detector wavelength=264 nm; retention time=8.0 min;ee>99%

EXAMPLE 422

To a 0° C. solution of Example 419, Part F compound (0.896 g, 2.23 mmol)in acetone (75 mL) was added Jones reagent (2.25 mL) dropwise. Thereaction mixture was stirred at RT for 30 min. Volatiles were removed invacuo and the residue was partitioned between water (60 mL) and EtOAc(200 mL). The organic phase was dried (MgSO₄) and concentrated in vacuoto give Part A compound which was used in the next step without furtherpurification.

[M+H]⁺=418.3.

To a 0° C. solution of Part A compound in CH₂Cl₂/MeOH (7 mL/7 mL) wasadded TMSCHN₂ in hexane (3 mL of a 2M solution). The reaction wasstirred at RT for 30 min. Volatiles were removed in vacuo and theresidue was chromatographed (SiO₂; continuous gradient from 100% hex to50:50 hex:EtOAc over 30 min) to give Part B compound (0.60 g, 62%).[M+H]⁺=432.4.

To a 0° C. solution of Part B compound (0.60 g; 1.4 mmol) in CH₃CN (17mL) was added a solution of ceric ammonium nitrate (1.5 g; 2.73 mmol) inH₂O (9.6 mL). The reaction mixture was stirred at 0° C. for 20 min, thenEtOAc (150 mL) was added. The organic phase was washed with saturatedaqueous sodium sulfite (15 mL), dried (MgSO₄) and concentrated in vacuo.The residue was chromatographed (SiO₂; stepwise gradient from 3:1 to 1:1hex:EtOAc) to give Part C compound (0.342 g; 75%) as a colorless oil. ¹HNMR (400 MHz, CDCl₃) δ 2.78 (dd, J=14.9, 8.4 Hz, 1H), 3.01 (dd, J=14.9,7.5 Hz, 1H), 3.57 (s, 3H), 3.81 (m, 1H), 4.24 (d, J=5.7 Hz, 1H), 4.98(bs, 1H), 5.03 (s, 2H), 6.70-6.85 (m, 3H), 7.13 (t, J=7.9 Hz, 1H),7.25-7.40 (m, 5H); [M+H]⁺=326.3.

To a solution of the Part C compound (27.9 mg, 0.086 mmol) in DCE (1.2mL) was added p-tert-butyl phenylboronic acid (31.3 mg, 0.176 mmol),Cu(OAc)₂ (16 mg 0.088 mmol), Et₃N (35 μL, 0.25 mmol), pyridine (25 μL.0.31 mmol) and 4 Å molecular sieves (150 mg; pre-dried at 400° C.overnight). Air was allowed to pass into the reaction mixture, which wasstirred at RT for 1.5 h. Volatiles were removed in vacuo and the residuewas chromatographed (SiO₂; 3:1 hex:EtOAc) to give Part D compound (38.6mg, 98%). [M+H]⁺=458.3.

A mixture of Part D compound (38.6 mg; 0.084 mmol) and 10% Pd/C (20 mg)in EtOAc (3 mL) was stirred under an atmosphere of H₂ (balloon) at RTfor 3 h, at which point the reaction was complete by HPLC. The catalystwas filtered off (Celite®) and the filtrate was concentrated in vacuo togive Part E compound (20 mg, 65%) as a solid.

[M+H]⁺=367.3.

A mixture of Part E compound (13.2 mg; 0.036 mmol), Example 23 Part Acompound (30 mg; 0.107 mmol) and powdered K₂CO₃ (23 mg; 0.167 mmol) inCH₃CN (1.5 mL) was stirred at 85° C. for 16 h, after which precipitateswere filtered. The filtrate was concentrated in vacuo and the residuewas chromatographed (SiO₂; stepwise gradient from 3:1 to 1.5:1hex:EtOAc) to give Part F compound (11.1 mg; 56%) as an oil.[M+H]⁺=553.4.

A solution of Part F compound (11.1 mg, 0.019 mmol) and aqueous LiOH.H₂O(2 mg in 0.6 mL H₂O, 0.047 mmol) in THF (0.8 mL) was stirred at RT for16 h, after which more LiOH.H₂O (2 mg, 0.047 mmol) was added. Afterstirring for another 24 h, the mixture was acidified to pH 4 with 1 Maqueous HCl. Volatiles were removed in vacuo and the residue waspartitioned between water (2 mL) and EtOAc (6 mL). The organic phase wasdried (MgSO₄) and concentrated in vacuo. The residue was purified bypreparative HPLC (continuous gradient over 12 min from 75:25 A:B to 100%B; A=90:10:0.1H₂O:MeOH:TFA; B=90:10:0.1 MeOH:H₂O:TFA; flow rate=20mL/min; detection at 220 nm; YMC ODS 20×100 mm column) to give Example422 (2.08 mg; 19%) as a viscous oil. [M+H]⁺=539.2.

EXAMPLES 423-427

Examples 423-427 were prepared in the same fashion as Example 422 (fromExample 422, Part C compound) using the appropriately substituted phenylboronic acids.

Example # R [M + H]⁺ 423

501.2 424

517.1 425

575.2 426

514.2 427

551.1

EXAMPLE 428

During the preparation of Example 427, at the final hydrolysis step, aslower eluting side product was isolated by preparative HPLC and wasdetermined to be the corresponding trans diastereomer (title compound).The epimerization was presumed to have occurred at the carboxylic acidstereocenter.

¹H NMR (400 MHz, CDCl₃) δ 2.24 (s, 3H), 2.86 (t, J=6.6 Hz, 2H),3.00-3.15 (m, 2H), 3.60-3.63 (m, 1H), 4.15 (t, J=6.6 Hz, 2H), 4.36 (s,1H), 6.68-6.85 (m, 3H), 7.10 (t, J=7.7 Hz, 1H), 7.25-7.50 (m, 6H), 7.55(s, 1H), 7.85-7.90 (m, 2H); [M+H]⁺=551.3.

EXAMPLE 429

To a 0° C. solution of Example 422, Part A compound (2.3 g, 5.73 mmol)in CH₂Cl₂ (9 mL) was added a solution of t-butyl2,2,2,-trichloroacetimidate (3.55 mL, 19.8 mmol) and BF₃.OEt₂ (0.305 ml,2.4 mmol). The mixture was stirred at RT for 2 h, after which excesssolid NaHCO₃ was added and stirring was continued for 5 min. Solids werefiltered off (Celite®) and the filtrate was concentrated in vacuo togive a residue which was chromatographed (SiO₂; continuous gradient from100% hex to 75:25 hex:EtOAc over 25 min, hold at 75:25 hex:EtOAc for 15min) to give Part A compound (1.66 g, 62%). [M+H]⁺=474.5

To a 0° C. solution of Part A compound (1.78 g; 1.64 mmol) in CH₃CN (50mL) was added aqueous ceric ammonium nitrate solution (4.12 g; 7.51 mmolin 28 mL of H₂O). The reaction mixture was stirred at 0° C. for 20 min,then was partitioned between EtOAc (250 mL) and saturated aqueous sodiumsulfite (50 mL). The organic phase was dried (MgSO₄) and concentrated invacuo. The residue was chromatographed (SiO₂; stepwise gradient from 3:1to 2:1 hex:EtOAc) to give Part B compound (1.13 g; 82%) as a colorlessoil. ¹H NMR (400 MHz, CDCl₃) δ 1.40 (s, 9H), 2.93 (dd, J=15.4, 7.9 Hz,1H), 3.06 (dd, J=14.9, 7.9 Hz, 1H), 3.83 (m, 1H), 4.24 (d, J=5.7 Hz,1H), 5.01 (s, 2H), 6.02 (bs, 1H), 6.84 (dd, J=8.4, 2.2 Hz, 1H), 6.86 (d,J=7.9 Hz, 1H), 6.93 (s, 1H), 7.21 (t, J=7.9 Hz, 1H), 7.30-7.45 (m, 5H);[M+Na]⁺=390.2.

The two enantiomers of racemic Part B compound were separatedpreparative HPLC (Chiralcel chiral AD 5×50 cm column; flow rate=45mL/min; isocratic mobile phase 92:8 A:B for 60 min, 85:15 A:B for 60min, 80:20 A:B for 60 min, 77:23 A:B for 60 min, where solventA=Heptane+0.1% TFA and solvent B=isopropanol+0.1% TFA). The fastereluting fraction was designated as Part C compound. [M+Na]⁺=390.2;[α]_(D)=+23.5° (c=0.41, CDCl₃, 25° C.).

Chiral analytical HPLC (Daicel Chiralcel AD 4.6×250 mm column): flowrate=1 mL/min; isocratic conditions=70:30 A:B, where A=heptane+0.1% TFAand B=IPA+0.1% TFA; detector wavelength=254 nm; retention time=9.43 min;ee>99%

The slower eluting fraction was designated as Part D compound.[M+Na]⁺=390.2; [α]_(D)=−17.9° (c=0.45, CDCl₃, 25° C.). Chiral analyticalHPLC (Daicel Chiralcel AD 4.6×250 mm column): flow rate=1 mL/min;isocratic conditions=70:30 A:B, where A=heptane+0.1% TFA and B=IPA+0.1%TFA; detector wavelength=254 nm; retention time=29.1 min; ee>97.5%

To a solution of Part C compound (270 mg, 0.75 mmol) in DCE (12 mL) wasadded p-tert-butyl phenylboronic acid (377 mg, 2.11 mmol), Cu(OAc)₂ (160mg, 0.88 mmol), Et₃N (0.511 μL, 3.67 mmol), pyridine (297 μL, 3.67 mmol)and 4 Å molecular sieves (200 mg; pre-dried at 400° C. overnight). Airwas allowed to pass into the reaction mixture, which was stirred at RTfor 5 h. The solid was filtered off (Celite®) and the filtrate wasconcentrated in vacuo to give a residue which was chromatographed (SiO₂;continuous gradient from 100% hex to 75:25 hex:EtOAc over 25 min, holdat 75:25 hex:EtOAc for 15 min) to give Part E compound (355 mg, 96%).[M+H]⁺=500.3.

A mixture of Part E compound (355 mg; 0.71 mmol) and 10% Pd/C (200 mg)in EtOAc (40 mL) was stirred under an atmosphere of H₂ (balloon) at RTfor 3 h, at which point the reaction was complete by HPLC. The catalystwas filtered off (Celite®) and the filtrate was concentrated in vacuo togive a residue which was chromatographed (SiO₂; stepwise gradient from4:1 to 3:1 hex:EtOAc to 1:1 hex:EtOAc) to give Part F compound as awhite solid (254 mg, 87%). [M+H]⁺=410.4.

A mixture of Part F compound (200 mg; 0.49 mmol), Example 23 Part Acompound (302 mg; 1.07 mmol) and powdered K₂CO₃ (270 mg; 1.96 mmol) inCH₃CN (15 mL) was stirred at 85° C. for 22 h, then was cooled to RT andthe precipitates were filtered off. The filtrate was concentrated invacuo and the residue was chromatographed (SiO₂; continuous gradientfrom 100% hex to 66%:33% hex:EtOAc over 20 min, hold at 66%:33%hex:EtOAc over 15 min) to give Part G compound as a solid (246 mg, 84%).

[M+H]⁺=595.5.

A solution of Part G compound (229 mg; 0.385 mmol) and TFA (5 mL) inCH₂Cl₂ (5 mL) was stirred at RT for 4 h. Volatiles were removed in vacuoand the residue was purified by preparative HPLC (Phenomenexreverse-phase Luna C18 5μ 30×250 mm column; flow rate=20 mL/min; 30 mincontinuous gradient from 80:20 B:A to 100% B+15 min hold time at 100% B,where solvent A=90:10:0.1 H₂O:MeOH:TFA and solvent B=90:10:0.1MeOH:H₂O:TFA) to give the product, which was then chromatographed (SiO₂;stepwise gradient from 15:1 to 10:1 CH₂Cl₂:MeOH) to give Example 429 asa white solid (145 mg; 70%). ¹H NMR (400 MHz, CDCl₃) δ 1.29 (s, 9H),2.40 (s, 3H), 3.00 (t, J=7.9 Hz, 2H), 3.23 (dd, J=14.5, 11.8 Hz, 1H),3.32 (dd, J=14.5, 3.6 Hz, 1H), 3.83-3.92 (m, 1H), 4.20-4.43 (m, 2H),4.50 (d, J=5.7 Hz, 1H), 6.79 (dd, J=7.9, 2.2 Hz, 1H), 6.93 (d, J=7.9 Hz,1H), 6.96 (s, 1H), 7.20-7.35 (m, 7H), 7.40-7.46 (m, 1H), 7.92-7.98 (m,2H); [M+H]⁺=539.1. [α]_(D)=−76.2° (c=0.5, CDCl₃, 25° C.); Absolutestereochemistry is tentatively assigned.

Chiral analytical HPLC (Daicel Chiralcel AD 4.6×250 mm column): flowrate=1 mL/min; isocratic conditions=70:30 A:B, where A=heptane+0.1% TFAand B=IPA+0.1% TFA; detector wavelength=254 nm; retention time=7.96 min;ee>99%

EXAMPLE 430

During preparation of Example 429, a slower eluting side product wasisolated by preparative HPLC and was determined to be the correspondingtrans epimer (title compound). The epimerization was presumed to haveoccurred at the carboxylic acid stereocenter. Relative and absolutestereochemistry is tentatively assigned.

¹H NMR (400 MHz, CDCl₃) δ 1.27 (s, 9H), 2.51 (s, 3H), 3.02-3.13 (m, 3H),3.35 (dd, J=15.9, 3.3 Hz, 1H), 3.73-3.80 (m, 1H), 3.83-3.92 (m, 1H),4.20-4.30 (m, 2H), 6.74 (d, J=7.7 Hz, 1H), 6.82 (d, J=7.7 Hz, 1H), 6.90(s, 1H), 7.19 (t, J=7.7 Hz, 1H), 7.25 (d, J=8.3 Hz, 2H), 7.33 (d, J=8.3Hz, 2H), 7.50-7.61 (m, 3H), 8.05-8.09 (m, 2H); [M+H]⁺=539.2.

EXAMPLE 431

The title compound was prepared as in Example 429 by starting fromExample 429 Part D compound. ¹H NMR: identical to Example 11;[M+H]⁺=539.1; [α]_(D)=+62.0° (c=0.5, CDCl₃, 25° C.). The absolutestereochemistry is tentatively assigned.

Chiral analytical HPLC (Daicel Chiralcel AD 4.6×250 mm column): flowrate=1 mL/min; isocratic conditions=70:30 A:B, where A=heptane+0.1% TFAand B=isopropanol+0.1% TFA; detector wavelength=264 nm; retentiontime=9.25 min; ee=99.3%

EXAMPLES 432-435

Examples 432-435 were prepared in a similar fashion to Example 429 (fromExample 429, Part F compound) using a variety of 2-substitutedphenyl-5-methyl oxazole-4-ethanol mesylates (prepared according togeneral procedure in Example 231, Part A compound) during alkylationstep.

Chiral HPLC Retention time Example # R [M + H]⁺ (min)* 432

569.1 7.15 433

569.1 8.94 434

573.1 8.34 435

573.0 11.18*Chiral analytical HPLC (Daicel Chiralcel AD 4.6 × 250 mm column): flowrate = 1 mL/min; isocratic conditions = 70:30 A:B, where A = heptane +0.1% TFA and B = isopropanol + 0.1% TFA; detector wavelength = 264 nm.

EXAMPLE 436

Part A compound was prepared exactly according to the method of Example47 Part B compound except that 3-hydroxy-benzaldehyde was used in placeof 4-hydroxybenzaldehyde.

HCl gas was bubbled through a solution of N-1-Boc-N-4-Fmoc-2-piperazinecarboxylic acid (5.0 g; 11 mmol) in MeOH (250 mL) at RT for 5 min. Thereaction was stirred at RT for 5 h, then was concentrated in vacuo. Theresidue was partitioned between EtOAc and 1N aqueous NaOH. The organicphase was dried (MgSO₄) and concentrated in vacuo to give Part Bcompound (3.8 g; 95%) as an oil.

To a RT solution of Part B compound (1.0 g; 2.7 mmol) and Part Acompound (840 mg; 2.7 mmol) in CH₂Cl₂ (150 mL) was added NaBH(OAc)₃ (930mg; 4.4 mmol). The reaction was stirred at RT for 18 h and then washedwith saturated aqueous NaHCO₃. The organic phase was dried (MgSO₄) andconcentrated in vacuo to furnish Part C compound (1.74 g; 97%) as anoil.

A solution of Part C compound (1.74 g; 2.65 mmol) and KOH (740 mg; 13.2mmol) in MeOH/H₂O (40 mL of a 1:1 solution) was stirred at RT for 18 h.Volatiles were removed in vacuo, and the residue was purified bypreparative HPLC (YMC reverse-phase ODS 30×250 mm column; detection at220 nm; flow rate=25 mL/min; continuous gradient from 100% A to 100% Bover 30 min+10 min hold time at 100% B, where A=90:10:0.1H₂O:MeOH:TFAand B=90:10:0.1 MeOH:H₂O:TFA) to provide Part D compound (510 mg; 40%)as an oil.

To a RT solution of Part D compound (50 mg; 0.11 mmol) and4-chlorophenyl chloroformate (28 mg; 0.14 mmol) in CH₂Cl₂ (2 mL) wasadded Et₃N (70 μL; 0.52 mmol). The reaction was stirred at RT for 16 hand then was concentrated in vacuo. The residue was purified bypreparative HPLC (YMC reverse-phase ODS 20×100 mm column; detection at220 nm; flow rate=20 mL/min; continuous gradient from 100% A to 100% Bover 30 min+10 min hold time at 100% B, where A=90:10:0.1H₂O:MeOH:TFAand B=90:10:0.1 MeOH:H₂O:TFA) to provide the title compound (28 mg; 44%)as a solid.

[M+H]⁺=577.4

EXAMPLES 437-441

Examples 437-441 of the invention were prepared according to the generalprocedure described for the synthesis of Example 436.

Example # R [M + H]⁺ 437

560.2 438

556.2 439

600.2 440

610.2 441

592.2

EXAMPLE 442

HCl gas was bubbled through a solution of N-1-Boc-N-4-Fmoc-2-piperazinecarboxylic acid (2.0 g; 4.4 mmol) in MeOH (100 mL) at RT for 5 min. Thereaction was stirred at RT for 3 h, then was concentrated in vacuo. Theresidue was partitioned between EtOAc and 1N aqueous NaOH. The organicphase was dried (MgSO₄) and concentrated in vacuo to give Part Acompound (1.2 g; 75%) as an oil.

To a RT solution of Part A compound (1.1 g; 3.0 mmol) and Example 47Part B compound (925 mg; 3.0 mmol)

in CH₂Cl₂ (150 mL) was added NaBH(OAc)₃ (930 mg; 4.4 mmol) at RT. Thereaction was stirred at RT for 18 h and then washed with saturatedaqueous NaHCO₃. The organic phase was dried (MgSO₄) and concentrated invacuo. The residue was purified by preparative HPLC (YMC reverse-phaseODS 20×100 mm column; detection at 220 nm; flow rate=20 mL/min;continuous gradient from 100% A to 100% B over 30 min+10 min hold timeat 100% B, where A=90:10:0.1H₂O:MeOH:TFA and B=90:10:0.1 MeOH:H₂O:TFA)to provide Part B compound (625 mg; 34%) as a solid.

A solution of Part B compound (315 mg; 0.5 mmol) and pyrrolidine (1.0mL; 12.0 mmol) in DMF (5 mL) was stirred at RT for 18 h. Volatiles wereremoved in vacuo, and the residue was purified by preparative HPLC (YMCreverse-phase ODS 30×250 mm column; detection at 220 nm; flow rate=25mL/min; continuous gradient from 100% A to 100% B over 30 min+10 minhold time at 100% B, where A=90:10:0.1H₂O:MeOH:TFA and B=90:10:0.1MeOH:H₂O:TFA) to provide Part C compound (105 mg; 50%) as an oil.

To a RT solution of Part C compound (20 mg; 0.05 mmol) and2-chloro-4-(trifluoromethyl)-pyrimidine (8.5 mg; 0.05 mmol) in CH₃CN (2mL) was added Cs₂CO₃ (15 mg; 0.05 mmol). The reaction mixture wasstirred at 60° C. for 18 h and then was concentrated in vacuo to givethe crude Part D compound, which was used in the next step withoutfurther purification.

A solution of crude Part D compound was MeOH/H₂O (2 mL of a 1:1solution) and KOH (5 mg, 0.09 mmol) was stirred at 60° C. for 18 h, thencooled to RT and concentrated in vacuo. The residue was purified bypreparative HPLC (YMC reverse-phase ODS 20×100 mm column; detection at220 nm; flow rate=20 mL/min; continuous gradient from 100% A to 100% Bover 30 min+10 min hold time at 100% B, where A=90:10:0.1H₂O:MeOH:TFAand B=90:10:0.1 MeOH:H₂O:TFA) to provide the title compound (13 mg; 50%)as a solid.

[M+H]⁺=568.6

EXAMPLES 443-445

Examples 443-445 of the invention were prepared according to the generalprocedure described for the synthesis of Example 442.

Example # R [M + H]⁺ 443

535.2 444

567.6 445

500.6

EXAMPLE 446

HCl gas was bubbled through a solution of N-4-Boc-N-1-Fmoc-2-piperazinecarboxylic acid (1.0 g; 2.2 mmol) in MeOH (100 mL) at RT for 5 min. Thereaction was stirred at RT for 2 h, then was concentrated in vacuo. Theresidue was partitioned between EtOAc and 1N aqueous NaOH. The organicphase was dried (MgSO₄) and concentrated in vacuo to give Part Acompound (0.8 g; 99%) as an oil.

To a RT solution of Part A compound (800 mg; 2.2 mmol) and Example 47Part B compound (670 mg; 2.2 mmol) in CH₂Cl₂ (100 mL) was addedNaBH(OAc)₃ (1.5 g; 7.0 mmol) The reaction was stirred at RT for 48 h andthen concentrated in vacuo. The residue was partitioned between EtOAcand saturated aqueous NaHCO₃. The organic phase was extracted, dried(MgSO₄) and concentrated in vacuo to furnish Part B compound (1.02 g;73%) as an oil.

A solution of Part B compound (1.0 g; 1.6 mmol) and pyrrolidine (3.2 mL;38.8 mmol) in DMF (15 mL) was stirred at RT for 18 h. Volatiles wereremoved in vacuo, and the residue was purified by preparative HPLC(Shimadzu VP reverse-phase ODS 20×250 mm column; detection at 254 nm;flow rate=20 mL/min; continuous gradient from 90% A to 100% B over 10min+10 min hold time at 100% B, where A=90:10:0.1H₂O:MeOH:TFA andB=90:10:0.1 MeOH:H₂O:TFA) to provide Part C compound (575 mg; 85%) as anoil.

To a RT solution of Part C compound (21 mg; 0.05 mmol) and phenylchloroformate (9.0 mg; 0.05 mmol) in CH₂Cl₂ (2 mL) was added Et₃N (30μL; 0.21 mmol). The reaction was stirred at RT for 16 h and then wasconcentrated in vacuo. The residue was dissolved in MeOH (2.0 mL) and2.0 mL of a 2.0M KOH solution was added. The reaction was stirred at RTfor 8 h, then was concentrated in vacuo. The residue was purified bypreparative HPLC (YMC reverse-phase ODS 20×100 mm column; detection at220 nm; flow rate=20 mL/min; continuous gradient from 90% A to 100% Bover 10 min+10 min hold time at 100% B, where A=90:10:0.1H₂O:MeOH:TFAand B=90:10:0.1 MeOH:H₂O:TFA) to provide the title compound (4.0 mg;15%) as a solid. [M+H]⁺=542.6

EXAMPLES 447-460

Examples 447-460 of the invention were prepared according to the generalprocedures described for the synthesis of Example 446.

Example # R [M + H]⁺ 447

494.5 448

572.6 449

478.5 450

464.5 451

555.6 452

526.6 453

556.6 454

560.6 455

556.6 456

577   457

572.6 458

592.6 459

542.6 460

422  

EXAMPLE 461

HCl gas was bubbled through a solution of N-1-Boc-N-4-Fmoc-2-piperazinecarboxylic acid (4.0 g; 8.8 mmol) in MeOH (200 mL) at RT for 5 min. Thereaction was stirred at RT for 2 h, then was concentrated in vacuo. Theresidue was partitioned between EtOAc and 1N aqueous NaOH. The organicphase was dried (MgSO₄) and concentrated in vacuo to give Part Acompound (1.4 g; 42%) as an oil.

A solution of Example 23 Part A compound (1.1 g; 3.7 mmol),4-hydroxy-benzoic acid methyl ester (570 mg; 3.7 mmol), and K₂CO₃ (515mg; 3.7 mmol) in CH₃CN (100 mL) was heated at 90° C. with stirring for18 h. The reaction mixture was cooled to RT, and the solvent was removedin vacuo. The residue was partitioned between EtOAc and 1 N NaOH. Theorganic phase was extracted, dried (MgSO₄) and concentrated in vacuo togive Part B compound (1.1 g; 91%).

A solution of Part B compound (1.1 g; 3.3 mmol) and potassium hydroxide(1.8 g; 33 mmol) in 1:1 MeOH:H₂O (100 mL) was stirred at RT for 18 h.The solvent was removed in vacuo, and the residue was partitionedbetween EtOAc and H₂O. The aqueous layer was brought to pH 5 using 1NHCl. The organic phase was extracted, dried (MgSO₄) and concentrated togive Part C compound (1.1 g; >99%).

A solution of Part C compound (1.1 g; 3.4 mmol) and oxalyl chloride (1.5mL; 17 mmol) in CH₂Cl₂ (100 mL) was stirred at RT for 18 h. A secondportion of oxalyl chloride (1.5 mL; 17 mmol) was added to the reaction,and the mixture stirred at RT for an additional 18 h. The solvent wasremoved in vacuo to give Part D compound (1.16 g; >99%).

To a RT solution of Part A compound (1.25 g mg; 3.4 mmol) and Part Dcompound (1.16 g; 3.4 mmol) in CH₂Cl₂ (100 mL) was added Et₃N (1.0 mL;6.8 mmol). The reaction was stirred at RT for 18 h and then concentratedin vacuo. The residue was partitioned between EtOAc and saturatedaqueous NaHCO₃. The organic phase was extracted, dried (MgSO₄) andconcentrated in vacuo to give Part E compound (1.7 g; 75%) as an oil.

A solution of Part E compound (1.7 g; 2.5 mmol) and pyrrolidine (5.2 mL;62.5 mmol) in DMF (10 mL) was stirred at RT for 18 h. Volatiles wereremoved in vacuo, and the residue was purified by preparative HPLC(Shimadzu VP reverse-phase ODS 20×250 mm column; detection at 254 nm;flow rate=20 mL/min; continuous gradient from 90:10 A:B to 100% B over10 min+10 min hold time at 100% B, where A=90:10:0.1H₂O:MeOH:TFA andB=90:10:0.1 MeOH:H₂O:TFA) to provide Part F compound (1.08 g; 96%) as anoil.

To a RT solution of Part F compound (50 mg; 0.11 mmol) and phenylchloroformate (21 mg; 0.13 mmol) in CH₂Cl₂ (2 mL) was added Et₃N (70 μL;0.48 mmol). The reaction was stirred at RT for 16 h and then wasconcentrated in vacuo. The residue was dissolved in MeOH (2.0 mL) andaqueous KOH (2.0 mL of a 2 M solution) was added. The reaction stirredat RT for 8 h and then was concentrated in vacuo. The residue waspurified by preparative HPLC (exactly as described in Part F) to providethe title compound (10.0 mg; 16%) as a solid.

[M+H]⁺=556.6

EXAMPLES 462-468

Examples 462-468 of the invention were prepared according to the generalprocedures described for the synthesis of Example 461.

Example # R [M + H]⁺ 462

586.6 463

536.6 464

478.5 465

507.6 466

555.6 467

569.2 468

540.6

EXAMPLE 469

To a RT solution of Example 461 Part F compound (50 mg; 0.11 mmol) and2-chloro-4-(trifluoromethyl)pyrimidine (21 mg; 0.11 mmol) in CH₃CN (2mL) was added Cs₂CO₃ (37 mg; 0.11 mmol). The reaction was stirred at RTfor 16 h, then at 60° C. for 4 h and then was concentrated in vacuo. Theresidue was dissolved in MeOH (2.0 mL) and aqueous KOH (2.0 mL of a 2.0Msolution) was added. The reaction was stirred at 60° C. for 18 h and wasconcentrated in vacuo. The residue was purified by preparative HPLC (YMCreverse-phase ODS 20×100 mm column; detection at 220 nm; flow rate=20mL/min; continuous gradient from 90% A to 100% B over 10 min+10 min holdtime at 100% B, where A=90:10:0.1H₂O:MeOH:TFA and B=90:10:0.1MeOH:H₂O:TFA) to provide the title compound (5.0 mg; 10%) as a solid.

[M+H]⁺=582.5

EXAMPLE 470

HCl gas was bubbled through a solution of N-1-Boc-N-4-Fmoc-2-piperazinecarboxylic acid (4.0 g; 8.8 mmol) in MeOH (200 mL) at RT for 5 min. Thereaction was stirred at RT for 2 h, then was concentrated in vacuo. Theresidue was partitioned between EtOAc and 1N aqueous NaOH. The organicphase was dried (MgSO₄) and concentrated in vacuo to give Part Acompound (1.4 g; 42%) as an oil.

Part B compound was prepared according to the procedure described forthe synthesis of Example 461 Parts B-D compounds, except that3-hydroxy-benzoic acid methyl ester was used in place of4-hydroxy-benzoic acid methyl ester.

A RT solution of Part A compound (1.25 g mg; 3.4 mmol), Part B compound(1.16 g; 3.4 mmol) and Et₃N (1.0 mL; 6.8 mmol) in CH₂Cl₂ (100 mL) wasstirred at RT for 18 h and then concentrated in vacuo. The residue waspartitioned between EtOAc and saturated aqueous NaHCO₃. The organicphase was extracted, dried (MgSO₄) and concentrated in vacuo to furnishPart C compound (2.2 g; 99%) as an oil.

A solution of Part C compound (2.2 g; 3.3 mmol) and pyrrolidine (6.8 mL;82.0 mmol) in DMF (10 mL) was stirred at RT for 18 h. Volatiles wereremoved in vacuo, and the residue was purified by preparative HPLC(Shimadzu VP reverse-phase ODS 20×250 mm column; detection at 254 nm;flow rate=20 mL/min; continuous gradient from 90% A to 100% B over 10min+10 min hold time at 100% B, where A=90:10:0.1H₂O:MeOH:TFA andB=90:10:0.1 MeOH:H₂O:TFA) to provide Part D compound (382 mg; 26%) as anoil.

To a RT solution of Part D compound (40 mg; 0.09 mmol) and phenylchloroformate (17 mg; 0.11 mmol) in CH₂Cl₂ (2 mL) was added Et₃N (60 μL;0.39 mmol). The reaction was stirred at RT for 16 h and then wasconcentrated in vacuo. The residue was dissolved in methanol (2.0 mL)and aqueous KOH (2.0 mL of a 2 M solution) was added. The reaction wasstirred at RT for 8 h and was concentrated in vacuo. The residue waspurified by preparative HPLC (as described for Part D compound) toprovide the title compound (11.0 mg; 22%) as a solid. [M+H]⁺=556.6

EXAMPLES 471-477

Examples 471-477 of the invention were prepared according to the generalprocedures described for the synthesis of Example 470.

Example # R [M + H]⁺ 471

586.6 472

536.6 473

507.6 474

555.6 475

569.6 476

540.6 477

478.5

EXAMPLE 478

To a RT solution of Example 470 Part D compound (40 mg; 0.09 mmol) and2-chloro-4-(trifluoromethyl)pyrimidine (17 mg; 0.09 mmol) in CH₃CN (2mL) was added Cs₂CO₃ (30 mg; 0.09 mmol). The reaction was stirred at RTfor 18 h and then was concentrated in vacuo. The residue was dissolvedin methanol (2.0 mL) and aqueous KOH (2.0 mL of a 2 M solution) wasadded. The reaction was stirred at RT for 18 h and was concentrated invacuo. The residue was purified by preparative HPLC (YMC reverse-phaseODS 20×100 mm column; detection at 220 nm; flow rate=20 mL/min;continuous gradient from 90% A to 100% B over 10 min+10 min hold time at100% B, where A=90:10:0.1 H₂O:MeOH:TFA and B=90:10:0.1 MeOH:H₂O:TFA) toprovide the title compound (3.0 mg; 6%) as a solid. [M+H]⁺=582.5

EXAMPLE 479

A solution of Example 242 Part A compound (65.6 mg; 0.126 mmol) in TFA(1 mL) and CH₂Cl₂ (4 mL) was stirred at RT for 1.5 h, then wasconcentrated in vacuo to give Part A compound as an oil (66 mg), whichwas used in the next step without further purification.

To a solution of Part A compound (9.4 mg, 0.0176 mmol) and NaHCO₃ (15mg; 0.178 mmol) in H₂O (0.7 mL) and THF (1 mL) was added phenylchloroformate (15 mg, 0.0285 mmol). The reaction was stirred at RT for 2h, then was partitioned between EtOAc and H₂O (1 mL each). The organicphase was concentrated in vacuo to give Part B compound as an oil.

A mixture of Part B compound and LiOH.H₂O (8 mg; 0.19 mmol) in THF/H₂O(1 mL of a 1:1 solution) was stirred at RT for 16 h, after which the pHwas adjusted to ˜5 with aqueous 1 M HCl. The mixture was extracted withEtOAc (2 mL). The combined organic extracts were concentrated in vacuoand the residue was purified by preparative HPLC (YMC reverse-phase ODS20×100 mm column; flow rate=20 mL/min; 10 min continuous gradient from30:70 B:A to 100% B+5 min hold-time at 100% B, where solventA=90:10:0.1H₂O:MeOH:TFA and solvent B=90:10:0.1 MeOH:H₂O:TFA) to givethe title compound (5.0 mg; 54%). [M+H]⁺=527.0

EXAMPLES 480-486

Examples 480-486 of the invention were prepared in a similar fashion tothe synthesis of Example 479 (from Example 479 Part A compound) using avariety of chloroformates.

Example # R [M + H]⁺ 480

479.1 481

493.1 482

493.1 483

507.1 484

539.0 485

541.0 486

557.0

EXAMPLE 487

To a solution of Example 419 Part F compound (2.0 g, 4.99 mmol) in THF(60 mL) was added LiBH₄ (0.18 g 8.26 mmol) and MeOH (6 ml). The reactionwas stirred at RT for 2 h. Volatiles were removed in vacuo and theresidue was partitioned between saturated aqueous NaHCO₃ (20 mL) andEtOAc (250 mL). The organic phase was dried (MgSO₄) and concentrated invacuo. The residue was chromatographed (SiO₂; continuous gradient from92:8 hex:EtOAc to 65:35 hex:EtOAc over 40 min, 65:35 hex:EtOAc for 20min) to give Part A compound (1.5 g, 75%) as a solid.

Monochloro-alane was prepared according to the literature procedure(Ref: Benito Alcaide et al, JOC 1999, 64, 9596). A solution of anhydrousAlCl₃ (400 mg 3.1 mmol) in dry Et₂O (5 mL) was added to a well-stirredsuspension of LiAlH₄ (118 mg, 1.73 mmol) in anhydrous Et₂O. The mixturewas heated at reflux for 30 min and cooled to RT. An aliquot of thismonochloro-alane solution in Et₂O (10 mL, ˜3.1 mmol) was transferred viacannula into a solution of Part A compound (0.7 g, 1.73 mmol) in THF (21mL) at RT. The mixture was stirred at RT for 1.5 h, then was partitionedbetween water (5 mL) and EtOAc (150 mL). The organic phase was dried(MgSO₄) and concentrated in vacuo; the residue was chromatographed(SiO₂; 3:2 hex:EtOAc) to give Part B compound (0.38 g; 56%) as acolorless oil, [M+H]⁺=390.3.

To a 0° C. solution of Part B compound (0.2 g; 0.52 mmol) in CH₃CN (3mL) was added aqueous ceric ammonium nitrate (0.422 g in 2.1 mL H₂O;0.77 mmol). The reaction was stirred at 0° C. for 30 min, then waspartitioned between EtOAc (10 mL) and saturated aqueous sodium sulfite(5 mL). The organic phase was dried (MgSO₄) and concentrated in vacuo togive crude Part C compound as an oil.

To a solution of Part C compound in THF (3 mL) was added aqueous NaHCO₃(0.128 g in 2 mL H₂O; 1.52 mmol) and 4-methoxyphenyl chloroformate (0.1ml, 0.67 mmol). The reaction mixture was stirred at RT for 30 min, thenwas partitioned between water (5 mL) and EtOAc (20 mL). The organicphase was dried (MgSO₄) and concentrated in vacuo; the residue waschromatographed (SiO₂; stepwise gradient from 2:1 to 1.5:1 hex:EtOAc) togive Part D compound (31.2 mg; 14% over 2 steps) as a colorless oil.

[M+H]⁺=434.3.

To a mixture of Dess-Martin periodinane (58 mg; 0.137 mmol) in CH₂Cl₂ (3mL) at RT was added a solution of Part D compound (40 mg; 0.093 mmol).The reaction was stirred at RT for 30 h. Volatiles were removed invacuo. The residue was chromatographed (SiO₂; 2:1 hex:EtOAc) to givePart E compound as an oil.

To a 0° C. solution of Part E compound in acetone (2 mL) was added Jonesreagent (˜3 drops). The reaction was stirred at RT for 30 min. Volatileswere removed in vacuo and the residue was partitioned between water (2mL) and EtOAc (5 mL). The organic phase was dried (MgSO₄) andconcentrated in vacuo to give crude Part F compound, which was used inthe next step without further purification. [M+H]⁺=448.3.

To a 0° C. solution of Part F compound in MeOH (1.5 mL) and CH₂Cl₂ (0.5mL) was added TMSCHN₂ (0.2 mL of a 2M solution in hexane; 0.4 mmol). Thereaction was stirred at RT for 2 h. Volatiles were moved in vacuo. Theresidue was chromatographed (SiO₂; stepwise gradient from 3:1 to 2:1hex:EtOAc) to give Part G compound (30 mg; 70% over two steps) as anoil. [M+H]⁺=462.3

A mixture of Part G compound (30 mg; 0.065 mmol) and 10% Pd/C (8 mg) inEtOAc (3.5 mL) was stirred under an atmosphere of H₂ (balloon) at RT for4 h, at which point the reaction was complete by HPLC. The catalyst wasfiltered off through Celite® and the filtrate was concentrated in vacuoto give crude Part H compound (17.0 mg, 71%) as a white solid which wasused in the next step without further purification.

[M+H]⁺=372.6.

A mixture of Part H compound (17 mg; 0.045 mmol), Example 23 Part Acompound (23 mg; 0.082 mmol) and powdered K₂CO₃ (16 mg; 0.115 mmol) inCH₃CN (2 mL) was stirred at 90° C. for 4 h, after which another portionof Example 23 Part A compound (20 mg; 0.082 mmol) was added. Thereaction mixture was stirred at 90° C. for another 14 h, cooled to RTand filtered. The filtrate was concentrated in vacuo. The residue waschromatographed (SiO₂; stepwise gradient from 3:1 to 1:1 hex:EtOAc) togive Part I compound as an oil.

A solution of Part I compound and aqueous LiOH (4 mg in 0.6 mL H₂O,0.095 mmol) in THF (1.5 mL) was stirred at RT for 6 h, then acidified topH 4 by the addition of 1M aqueous HCl. Volatiles were removed in vacuoand the residue was partitioned between water (2 mL) and EtOAc (10 mL).The organic phase was dried (MgSO₄) and concentrated in vacuo. Theresidue was purified by preparative HPLC (continuous gradient from 70:30A:B to 100% B; A=90:10:0.1H₂O:MeOH:TFA; B=90:10:0.1 MeOH:H₂O:TFA; 12 minrun @20 mL/min; detection at 220 nm; YMC ODS 20×100 mm column) to givethe title compound (4.0 mg; 16%) as a viscous oil.

¹H NMR (400 MHz, CD₃OD) δ 2.28 (3H, s), 2.55-2.65 (1H, m), 2.89-2.90(3H, m),3.2-3.3 (1H, m), 3.69 (3H, s), 3.70-4.10 (2H, m),4.14 (2H, t,J=6.6 Hz), 4.70-4.90 (1H, m), 6.60-7.10 (m, 8H), 7.35-7.40 (3H, m),7.80-7.90 (2H, m)

[M+H]+=543.2

EXAMPLE 488

To a solution of crude Example 310 (˜100 mg) in CH₂Cl₂ (5 mL) was addedoxalyl chloride (1.4 mL of a 1 mL solution in CH₂Cl₂; 1.4 mmol) and onedrop of DMF. The solution was stirred for 18 h at RT and thenconcentrated in vacuo to give Part A compound.

To a solution of diazomethane in 20 mL of Et₂O (prepared from 10 mL of50% aqueous KOH and 1-methyl-3-nitro-1-nitrosoguanidine (0.411 g; 2.8mmoL) in 20 mL of Et₂O at 0° C. according to the procedure described inExample 281 Part C), was added a solution of Part A compound in CH₂Cl₂(2 mL) and Et₂O (10 mL). The solution was stirred for 4 h at RT andconcentrated in vacuo. The residue was chromatographed (SiO₂; 4:1hex:EtOAc) to give Part B compound.

To a solution of Part B compound in MeOH (5 mL) was added silverbenzoate (64 mg; 0.28 mmol) and Et₃N (0.2 mL) at RT. The mixture wasstirred at RT for 4 h and then filtered. Aqueous 1 N KOH (2 mL) wasadded to the filtrate and the mixture was stirred for 3 h at RT, thenwas neutralized with 1 N HCl, concentrated in vacuo and partitionedbetween brine and EtOAc. The organic layer was washed with brine andconcentrated in vacuo. The residue was purified by HPLC (YMCreverse-phase ODS 20×100 mm column; flow rate=20 mL/min; 10 mincontinuous gradient from 30:70 B:A to 100% B+5 min hold-time at 100% B,where solvent A=90:10:0.1H₂O:MeOH:TFA and solvent B=90:10:0.1MeOH:H₂O:TFA) to give the title compound (7 mg; 7%).

[M+H]⁺=553.2

1. A compound having the structure

wherein Z¹ is (CH₂)_(q); Z² is C═O;

D is —CH═ or C═O or (CH₂)_(m) where m is 0, 1, 2 or 3; n=0; q=0; Q is Cor N; A is (CH₂)_(x) where x is 1 to 5; or A is (CH₂)_(x) ¹, where x¹ is1 to 5, with an alkenyl bond or an alkynyl bond embedded anywhere in thechain; or A is —(CH₂)_(x) ²—O—(CH₂)_(x) ³— where x² is 0 to 5 and x³ is0 to 5, provided that at least one of x² and x³ is other than 0; B is abond or is (CH₂)_(x) ⁴ where x⁴ is 1 to 5; X is CH or N; X₂ is C, N, Oor S; X₃ is C, N, O or S; X₄ is C, N, O or S; X₅ is C, N, O or S; X₆ isC, N, O or S; provided that at least one of X₂, X₃, X₄ X₅ and X₆ is N;and at least one of X₂, X₃, X₄ X₅ and X₆ is C; R¹ is H or alkyl; R² isH, alkyl, alkoxy, halogen, amino or substituted amino; R^(2a), R^(2b)and R^(2c) may be the same or different and are selected from H, alkyl,alkoxy, halogen, amino, substituted amino or cyano; R³ is selected fromH, alkyl, arylalkyl, aryloxycarbonyl, alkyloxycarbonyl,alkynyloxycarbonyl, alkenyloxycarbonyl, arylcarbonyl, alkylcarbonyl,aryl, heteroaryl, cycloheteroalkyl, heteroarylcarbonyl,heteroaryl-heteroarylalkyl, alkylcarbonylamino, heteroaryloxycarbonyl,cycloheteroalkyloxycarbonyl, heteroarylalkyl, aminocarbonyl, substitutedaminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, heteroarylalkenyl,cycloheteroalkyl-heteroarylalkyl; hydroxyalkyl, alkoxy,alkoxyaryloxycarbonyl, arylalkyloxycarbonyl, alkylaryloxycarbonyl,arylheteroarylalkyl, arylalkylarylalkyl, aryloxyarylalkyl,haloalkoxyaryloxycarbonyl, alkoxycarbonylaryloxycarbonyl,aryloxyaryloxycarbonyl, arylsulfinylarylcarbonyl, arylthioarylcarbonyl,arylalkenyloxycarbonyl, heteroaryloxyarylalkyl, aryloxyarylcarbonyl,arylcarbonylamino, heteroarylcarbonylamino, alkoxycarbonylamino,aryloxycarbonylamino, heteroaryloxycarbonylamino,heteroaryl-heteroarylcarbonyl, alkylsulfonyl, alkenylsulfonyl,heteroaryloxycarbonyl, cycloheteroalkyloxycarbonyl, heteroarylalkyl,aminocarbonyl, substituted aminocarbonyl, alkylaminocarbonyl,arylaminocarbonyl, heteroarylalkenyl, cycloheteroalkyl-heteroarylalkyl;hydroxyalkyl, alkoxy, alkoxyaryloxycarbonyl, arylalkyloxycarbonyl,alkylaryloxycarbonyl, arylheteroarylalkyl, arylalkylarylalkyl,aryloxyarylalkyl, haloalkoxyaryloxycarbonyl,alkoxycarbonylaryloxycarbonyl, aryloxyaryloxycarbonyl,arylsulfinylarylcarbonyl, arylthioarylcarbonyl,alkoxycarbonylaryloxycarbonyl, arylalkenyloxycarbonyl,heteroaryloxyarylalkyl, aryloxyarylcarbonyl,aryloxyarylalkyloxycarbonyl, arylalkenyloxycarbonyl, arylalkylcarbonyl,aryloxyalkyloxycarbonyl, arylalkylsulfonyl, arylthiocarbonyl,arylalkenylsulfonyl, heteroarylsulfonyl, arylsulfonyl, alkoxyarylalkyl,heteroarylalkoxycarbonyl, arylheteroarylalkyl, alkoxyarylcarbonyl,aryloxyheteroarylalkyl, heteroarylalkyloxyarylalkyl, arylarylalkyl,arylalkenylarylalkyl, arylalkoxyarylalkyl, arylcarbonylarylalkyl,alkylaryloxyarylalkyl, arylalkoxycarbonylheteroarylalkyl,heteroarylarylalkyl, arylcarbonylheteroarylalkyl,heteroaryloxyarylalkyl, arylalkenylheteroarylalkyl, arylaminoarylalkyl,or aminocarbonylarylarylalkyl; E is CH; Z is (CH₂)_(x) ⁵ where x⁵ is 0;(CH₂)_(x), (CH₂)_(x) ¹, (CH₂)_(x) ², (CH₂)_(x) ³, and (CH₂)_(x) ⁴,(CH₂)_(m), may be optionally substituted; Y is CO₂R⁴ where R⁴ is H oralkyl; including all stereoisomers thereof, prodrug esters thereof, andpharmaceutically acceptable salts thereof.
 2. The compound as defined inclaim 1 wherein X is CH.
 3. The compound as defined in claim 1 wherein Ais —CH₂)_(x) ²—O—.
 4. The compound as defined in claim 1 wherein Q is C.5. The compound as defined in claim 1 wherein B is a bond.
 6. Thecompound as defined in claim 1 wherein is


7. (canceled)
 8. (canceled)
 9. The compound as defined in claim 1 whereX is CH.
 10. (canceled)
 11. The compound as defined in claim 1 havingthe structure

wherein

R¹ is alkyl; R^(2a) is alkyl, alkoxy or halogen; x² is 1 to 3; D is —CH═or (CH₂)_(m) where m is 0 or (CH₂)_(n) is CH₂ or CH-alkyl; X is CH; X₂,X₃, X₄, X₅, and X₆ represent a total of 1, 2 or 3 nitrogens; R³ isalkoxycarbonyl, aryl, heteroaryl, aryloxycarbonyl or arylalkyl; and Y isCO₂R⁴; or a pharmaceutically acceptable salt thereof.
 12. (canceled) 13.The compound as defined in claim 1 having the structure

or a pharmaceutically acceptable salt thereof.
 14. A pharmaceuticalcomposition comprising a compound as defined in claim 1 and apharmaceutically acceptable carrier therefor.
 15. A method for treatingdiabetes, especially Type 2 diabetes, and related diseases such asinsulin resistance, hyperglycemia, hyperinsulinemia, elevated bloodlevels of fatty acids or glycerol, hyperlipidemia, obesity,hypertriglyceridemia, inflammation, Syndrome X, atherosclerosis, andrelated diseases, which comprises administering to a patient in need ofsuch treatment a therapeutically effective amount of a compound asdefined in claim
 1. 16. (canceled)
 17. A pharmaceutical combinationcomprising a compound as defined in claim 1 and a lipid-lowering agent,an antidiabetic agent, an anti-obesity agent, a platelet aggregationinhibitor, or an antiosteoporosis agent.
 18. The composition as definedin claim 17 wherein the antidiabetic agent is 1, 2, 3 or more of abiguanide; a sulfonyl urea; a glucosidase inhibitor; a PPAR γ agonist; aPPAR α/γ dual agonist; an SGLT2 inhibitor; a DP4 inhibitor; an aP2inhibitor; an insulin sensitizer; a glucagon-like peptide-l (GLP-l);insulin and/or a meglitinide; the anti-obesity agent is a beta 3adrenergic agonist, a lipase inhibitor, a serotonin (and dopamine)reuptake inhibitor, a thyroid receptor agonist, a cannabinoid receptor-1antagonist and/or an anorectic agent; the lipid lowering agent is an MTPinhibitor, an HMG CoA reductase inhibitor, a squalene synthetaseinhibitor, a fibric acid derivative, an upregulator of LDL receptoractivity, a lipoxygenase inhibitor, a farnesoid receptor (FXR) agonist,a liver X receptor (LXR) agonist, a CETP inhibitor or an ACAT inhibitor;the antihypertensive agent is an ACE inhibitor, angiotensin II receptorantagonist, NEP/ACE inhibitor, calcium channel blocker or a β-adrenergicblocker.
 19. The composition as defined in claim 18 wherein theantidiabetic agent is 1, 2, 3 or more of metformin, glyburide,glimepiride, glipyride, glipizide, chlorpropamide, gliclazide, acarbose,miglitol, pioglitazone, rosiglitazone, balaglitazone, insulin,Gl-262570, isaglitazone, JTT-501, NN-2344, L895645, YM-440, R-119702,AJ9677, repaglinide, nateglinide, KAD1129, AR-HO39242, GW-409544,KRP297, AZ-242, AC2993, LY315902, P32/98 and/or NVP-DPP-728A, theanti-obesity agent is orlistat, ATL-962, AJ9677, L750355, CP331648,sibutramine, topiramate, axokine, dexamphetamine, phentermine,phenylpropanolamine, rimonabant (SR-141716) and/or mazindol, the lipidlowering agent is pravastatin, lovastatin, simvastatin, atorvastatin,fluvastatin, itavastatin, visastatin, rosuvastatin, pitavastatin,fenofibrate, gemfibrozil, clofibrate, avasimibe, ezetimibe, TS-962,MD-700, cholestagel, niacin and/or LY295427, the antihypertensive agentis an ACE inhibitor which is captopril, fosinopril, enalapril,lisinopril, quinapril, benazepril, fentiapril, ramipril or moexipril; anNEP/ACE inhibitor which is omapatrilat,[S[(R*,R*)]-hexahydro-6-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-2,2-dimethyl-7-oxo-1H-azepine-1-aceticacid (gemopatrilat) or CGS 30440; an angiotensin II receptor antagonistwhich is irbesartan, losartan, telmisartan or valsartan; amlodipinebesylate, prazosin HCl, verapamil, nifedipine, nadolol, propranolol,carvedilol, or clonidine HCl, the platelet aggregation inhibitor isaspirin, clopidogrel, ticlopidine, dipyridamole or ifetroban.